Alcohol-resistant drug formulations

ABSTRACT

The invention relates to modified release oral formulations of therapeutic agents, including gamma hydroxybutyrate (GHB), paracetamol, codeine or oxycodone, which are resistant to alcohol induced dose dumping. Provided are formulations that have improved resistance to rapid release of the active ingredient in the presence of increasing amounts of alcohol. Also provided are formulations that can reduce or prevent the release of the active ingredient following exposure to alcohol-containing media. The invention also relates to methods of making the formulations, and methods of their use for the treatment of sleep disorders such as apnea, sleep time disturbances, narcolepsy, cataplexy, sleep paralysis, hypnagogic hallucination, sleep arousal, insomnia, and nocturnal myoclonus.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/688,797, filed Nov. 19, 2019, which claims priority from U.S.Provisional Application Ser. No. 62/769,380 filed Nov. 19, 2018 and U.S.Provisional Application Ser. No. 62/769,382 filed Nov. 19, 2018, each ofwhich is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to modified release formulations oftherapeutic agents such as gamma hydroxybutyrate (GHB or oxybate),paracetamol, opioids or opiates that are resistant to alcohol-induceddose dumping. The invention is particularly applicable to therapeuticagents whereby there is a serious clinical consequence of an alcoholinduced dose dumping event (e.g. GHB, paracetamol, codeine oroxycodone). The invention also relates to methods for safelyadministering such therapeutic agents (e.g. GHB, paracetamol, codeine oroxycodone), methods of making the formulations, and methods of their usefor the treatment of sleep disorders such as apnea, sleep timedisturbances, narcolepsy, cataplexy, sleep paralysis, hypnagogichallucination, sleep arousal, insomnia, and nocturnal myoclonus.

BACKGROUND OF THE INVENTION

“Dose dumping” refers to the unintended, rapid release of a drugcontained in a dosage form within a short period of time. Dose dumpingposes a significant risk to patients because of safety issues and/ordiminished efficacy, particularly in oral dosage forms where the activedrug may be present in relatively high amounts and especially when it isintended to release the drug slowly. Many modified release oral dosageforms are vulnerable to “alcohol-induced dose dumping” which, dependingon the drug being “dumped”, can also cause serious side effects.

Certain drugs, including GHB (commercially sold as Xyrem®), may causerespiratory depression or distress or changes in alertness if largeamounts are released due to dose dumping. The FDA requires strictImportant Safety Information to be provided with such medicines andwhich must clearly outline that one should not drink alcohol when takingthese drugs. The onus thus falls on the user to regulate the timing oftheir alcohol consumption in comparison to when they take the drug. Asalcohol is known to impair judgement, it runs the risk that someone whois intoxicated may still ingest these types of agents even afterconsuming significant amounts of alcohol. Thus there is a need formodified release formulations that can prevent or delay the release ofsuch drugs in the presence of alcohol which is either intentionally oraccidentally co-ingested.

Development of modified release oral dosage forms have been studied formany years and they often use multiple release-rate-controllingmechanisms. Typical release-rate-controlling mechanisms includeswellable polymers, gel matrixes and polymeric coatings.

The problem of dose dumping in the presence of alcohol has not yet beensatisfactorily resolved. Accordingly, there exists a need in the art toprovide modified release oral dosage forms which have reduced potentialfor alcohol induced dose dumping, particularly at increasingconcentrations of alcohol. The inventors have surprisingly found that bycoating a drug-containing core with a specific mixture of polymers,normal release of the drug occurs when exposed to low levels of alcohol;however, drug release is rapidly and significantly reduced as the amountof alcohol increases.

SUMMARY OF THE INVENTION

The present invention overcomes deficiencies in the prior art byproviding drug compositions that are resistant to alcohol induced dosedumping. One embodiment of a drug is gamma-hydroxybutyrate (GHB) or asalt thereof. Other embodiments are drugs used for mild, moderate and/orsevere pain, including paracetamol, opioids or opiates. In certainembodiments the opioid or opiate is selected from codeine, morphine,methadone, buprenorphine, hydrocodone or oxycodone. Compositions of theinvention can also suppress the release of these drugs followingexposure to alcohol and have adjusted drug product dissolutionproperties when the composition is exposed to increasing concentrationsof alcohol. One embodiment of the present invention also providesmethods to treat a number of conditions treatable by GHB, paracetamol,an opioid and/or opiate referred to herein as “therapeutic categories.”Therapeutic categories for the present invention include, but are notlimited to, sleeping disorders, drug abuse, alcohol and/or opiatewithdrawal, a reduced level of growth hormone, anxiety, analgesia(including the treatment of mild, moderate and/or severe pain; includingacute, chronic, breakthrough, somatic, visceral or neuropathic pain),effects in certain neurological disorders, such as Parkinson's Disease,depression, certain endocrine disturbances and tissue protectionfollowing hypoxia/anoxia such as in stroke or myocardial infarction, oran increased level of intracranial pressure or other conditionstreatable with GHB, paracetamol, an opioid or opiate. Prevention ofalcohol induced dose dumping is particularly pertinent for alcohol,opioid and/or opiate withdrawal.

One embodiment of the invention is an oral formulation with increasedresistance to alcohol-mediated dissolution comprising at least onepopulation of drug carrier cores comprising at least one therapeuticagent; wherein said core is coated with one or more functional coatings;and wherein said one or more functional coatings comprises a polymerblend of cellulose polymers and polymethacrylates. In some embodiments,the drug carrier core comprises granules, nanoparticles,micro-particles, beads, pellets, mini-tablets, tablets and/or capsules(hard and/or soft gelatin), or a combination thereof. In otherembodiments, the drug carrier core comprises drug crystals. Smaller drugcarrier cores or drug crystals may see thicker film coats due to highersurface area and substantially thicker gel layers in the presence ofethanol. In some embodiments, the drug carrier core can be the sizeand/or shape of a pellet, bead, mini-tablet or tablet.

In some embodiments, the polymer blend comprises ethyl cellulose and apolymethacrylate. In certain embodiments, the ethyl cellulose and apolymethacrylate polymer are present at a weight ratio of ethylcellulose:polymethacrylate polymer from 50:1 to 1:50, 25:1 to 1:25, 10:1to 1:10, 5:1 to 1:5 or 3:1 to 1:3. In specific embodiments, the ethylcellulose and a polymethacrylate polymer are present at a weight ratioof ethyl cellulose:polymethacrylate polymer from 3:1 to 1:3. In otherembodiments, the ethyl cellulose and a polymethacrylate polymer arepresent at a weight ratio of ethyl cellulose:polymethacrylate polymerfrom 3:1 to 1:3, 2:1 to 1:2, or 1:1. In still other embodiments, theethyl cellulose and a polymethacrylate polymer are present at a weightratio of ethyl cellulose:polymethacrylate polymer of 3:1, 2:1, 3:2, 1:1,2:3, 1:2, or 1:3. In some embodiments, the polymethacrylate is a methylmethacrylate. In other embodiments, the polymethacrylate is amethacrylic acid-ethyl acrylate co-polymer. In specific embodiments, thepolymethacrylate is methacrylic acid-ethyl acrylate co-polymer 1:1.

In certain embodiments, the polymer blend comprises at least twoalcohol-soluble polymers.

In other embodiments, the polymer blend comprises at least one polymerwith pH-dependent dissolution and at least one polymer withpH-independent dissolution properties.

In some embodiments, the polymer blend comprises at least two polymerswith pH-independent dissolution properties or at least two polymers withpH-dependent dissolution properties.

In some embodiments, the polymer with pH-independent dissolutionproperties is selected from ethyl cellulose and/or ethyl acrylate-methylmethacrylate co-polymer and/or ethyl acrylate-methylmethacrylate-trimethylammonioethyl methacrylate chloride co-polymer. Inspecific embodiments, the ethyl acrylate-methylmethacrylate-trimethylammonioethyl methacrylate chloride co-polymer ispresent at a ratio from about 1:2:0.1 to 1:2:0.2.

In some embodiments, the polymer with pH-dependent dissolutionproperties is selected from methacrylic acid ethyl acrylate co-polymerand/or butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methylmethacrylate co-polymer and/or methacrylic acid methyl methacrylateco-polymer and/or methyl acrylate-methyl methacrylate-methacrylic acidco-polymer. In specific embodiments, the methacrylic acid-ethyl acrylateco-polymer is methacrylic acid-ethyl acrylate co-polymer 1:1.

In some embodiments, the oral formulation further comprises a secondpolymer film coat or top coat. In certain embodiments, the secondpolymer film coat or top coat comprises a single polymer (preferablyethylcellulose), or a blend of at least two polymers (ethylcellulose anda polymethacrylate for example). In certain embodiments, the secondpolymer film coat or top coat further comprises a polysaccharide gumsuch as acacia gum, guar gum, tragacanth gum or xanthan gum. In certainembodiments, the second polymer film coat or top coat comprises analginic acid, or salt thereof.

In some embodiments, the therapeutic agent is selected from GHB andpharmaceutically acceptable salts, hydrates, tautomers, solvates,isotopologues and complexes of GHB. Preferably, the GHB salt is selectedfrom sodium oxybate, calcium oxybate, potassium oxybate, magnesiumoxybate or combinations thereof, See U.S. Pat. No. 8,591,922 or9,132,107 which are hereby incorporated by reference in theirentireties. In some embodiments, the GHB is present as a prodrug ordrug-conjugate. In other embodiments, the therapeutic agent is selectedfrom paracetamol, an opioid or an opiate and pharmaceutically acceptablesalts, hydrates, tautomers, solvates, isotopologues and complexes ofparacetamol, an opioid or an opiate. In specific embodiments, thetherapeutic agent is selected from paracetamol, codeine or oxycodone andpharmaceutically acceptable salts, hydrates, tautomers, solvates,isotopologues and complexes of paracetamol, codeine or oxycodone.

In some embodiments, provided is an oral formulation that is resistantto alcohol-induced dose dumping. In certain embodiments, provided is anoral formulation wherein the composition is adjusted to achieve therequired drug release kinetics, including, but not limited to,immediate, sustained or delayed release, to meet the target in vivopharmacokinetic profile for said drug.

In some embodiments, the oral formulation comprises a population of drugcarrier cores comprising the therapeutic agent. In other embodiments,the oral formulation comprises two or more populations of drug carriercores comprising the therapeutic agent.

In some embodiments, the oral formulation comprises a one or morepopulations of immediate release (IR) drug carrier cores that provide animmediate release of the therapeutic agent in the absence of ethanol. Inspecific embodiments, the IR drug carrier cores release between about70% and about 100% of the therapeutic agent after about 5 minutes toabout 60 minutes of being in an aqueous buffer. In certain embodiments,the IR drug carrier cores release between about 70% and about 100% ofthe therapeutic agent after about 5 minutes to about 60 minutes of beingin a aqueous buffer. In particular embodiments, the IR drug carriercores release between about 70-80%, 70-90%, 70-100%, 80-90%, 80-100%, or90-100% of the therapeutic agent in about 5-10, 5-15, 5-20, 5-30, 5-45,5-60, 10-15, 10-20, 10-30, 10-45, 10-60, 15-30, 15-45, 15-60, 20-30,20-45, 20-60, 30-45, 30-60, or 45-60 minutes.

In some embodiments, the oral formulation comprises one or morepopulations of sustained release (SR) drug carrier cores that provide asustained release profile of the therapeutic agent in the absence ofethanol. In specific embodiments, the sustained release profile providesnot more than about 10% to about 50% release of the therapeutic agentwithin about 1 hour of being in an aqueous buffer, between about 20% toabout 70% release within about 2 hours to about 4 hours of being in anaqueous buffer, and between about 50% to about 80% release within about4 hours to about 10 hours of being in an aqueous buffer.

In some embodiments, the oral formulation comprises one or morepopulations of delayed release (DR) drug carrier cores that provide adelayed release profile of the therapeutic agent in the absence ofethanol. In some embodiments, release of the therapeutic agent isdelayed during gastric transit following ingestion. In specificembodiments, release of the therapeutic agent is delayed during gastrictransit following ingestion and having not more than about 0% to 40%release of the therapeutic agent within about 1 hour to about 2 hours ofbeing in an acidic aqueous buffer (pH<5). In other embodiments, releaseof the therapeutic agent is delayed during exposure to the acidicaqueous buffer (pH<5), and then release of the therapeutic agentincreases after the formulation is subsequently exposed to a non-acidic(pH>5) aqueous solution such that release of the therapeutic agentincreases to between about 50% to about 100% release within about 1 hourof being in said non-acidic aqueous solution; or to between about 10% toabout 70% release within about 1 hour to about 4 hours of being in saidnon-acidic aqueous solution.

In some embodiments, the release rate of the therapeutic agent from theformulation demonstrates no significant change in release rate whenexposed to between about 5 to about 40% ethanol (v/v) as compared towhen said ethanol is not present. In certain embodiments, the releaserate of the therapeutic agent from the formulation when exposed tobetween about 5% to about 40% ethanol (v/v) is within about 1%, 2%, 3%,4%, 5%, 7%, 8%, 9%, 10%, 15%, 20% or 25% or more of the release whenethanol is not present. In some embodiments, the release rate of thetherapeutic agent from the formulation demonstrates no significantchange in release rate when exposed to about 5%, about 10%, about 15%,about 20%, about 25%, about 30%, about 35%, or about 40% ethanol (v/v)as compared to when said ethanol is not present. In certain embodiments,the release rate of the therapeutic agent from the formulation whenexposed to between about 5% to about 40%, or about 5%, about 10%, about15%, about 20%, about 25%, about 30%, about 35%, or about 40% ethanol(v/v) is within about 1%, 2%, 3%, 4%, 5%, 7%, 8%, 9%, 10%, 15%, 20% or25% or more of the release when ethanol is not present. In specificembodiments, the release rate of the therapeutic agent is measured usingan in vitro dissolution test and the about 5% to about 40%, about 5%,about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, orabout 40% ethanol (v/v) is present in the acidic aqueous buffer. In someembodiments, the F2 Similarity Factor is used to determine if therelease rate of the therapeutic agent from the drug carrier coresdemonstrates no significant change when exposed to between about 5% toabout 40%, or about 5%, about 10%, about 15%, about 20%, about 25%,about 30%, about 35%, or about 40% ethanol (v/v) as compared to whensaid ethanol is not present. The F2 Similarity Factor is described inShah, V P et al., In vitro Dissolution Profile Comparison—Statistics andAnalysis of the Similarity Factor, f2. Pharm Research, (1998) 15 (6),which is incorporated herein by reference in its entirety.

In some embodiments, the release rate of the therapeutic agent from theformulation or drug carrier core decreases by at least 5%, at least 10%,at least 20%, at least 30%, at least 40%, at least 50%, at least 60% ormore, when exposed to about 5%, about 10%, about 15%, about 20%, about25%, about 30%, about 35%, or about 40% ethanol (v/v) as compared to therelease rate of said therapeutic agent when ethanol is not present.

In some embodiments, the release rate of the therapeutic agent from theformulation or drug carrier core decreases by no more than about 5%,about 10%, or about 15%, when exposed to about 5% ethanol (v/v) ascompared to the release rate of said therapeutic agent when exposed toethanol at levels greater than 5% (v/v).

In some embodiments, the release rate of the therapeutic agent from theformulation or drug carrier core decreases by no more than about 5%,about 10%, or about 15%, when exposed to about 10% ethanol (v/v) ascompared to the release rate of said therapeutic agent when exposed toethanol at levels greater than 10% (v/v).

In some embodiments, the release rate of the therapeutic agent from theformulation or drug carrier core decreases by no more than about 5%,about 10%, or about 15%, when exposed to about 15% ethanol (v/v) ascompared to the release rate of said therapeutic agent when exposed toethanol at levels greater than 15% (v/v).

In some embodiments, the release rate of the therapeutic agent from theformulation or drug carrier core decreases by no more than about 5%,about 10%, or about 15%, when exposed to about 20% ethanol (v/v) ascompared to the release rate of said therapeutic agent when exposed toethanol at levels greater than 20% (v/v).

In some embodiments, the release rate of the therapeutic agent from theformulation or drug carrier core decreases when exposed to between about10% to about 40% ethanol (v/v) as compared to when said ethanol is notpresent. In some embodiments, the release rate of the therapeutic agentfrom the formulation demonstrates an ethanol concentration-dependentdecrease in release when between about 10% to about 40% ethanol (v/v) isadded to the acidic aqueous buffer. Thus in certain embodiments, therelease rate of the therapeutic agent from the formulation decreases asthe concentration of ethanol increases. In certain embodiments, theethanol concentration is about at least about 10%, 15%, 20%, 25%, 30%,35%, 40%, or greater than 40% (v/v). In specific embodiments, theethanol concentration is at least about 10% (v/v) or more; at leastabout 20% (v/v) or more; at least about 30% (v/v) or more; or at leastabout 40% (v/v) or more.

In some embodiments, the release rate of the therapeutic agent from theformulation or drug carrier core decreases when exposed to between about5% to about 40% ethanol (v/v) as compared to when said ethanol is notpresent. In some embodiments, the release rate of the therapeutic agentfrom the formulation demonstrates an ethanol concentration-dependentdecrease in release when between about 5% to about 40% ethanol is addedto the acidic aqueous buffer. Thus in certain embodiments, the releaserate of the therapeutic agent from the formulation decreases as theconcentration of ethanol increases. In certain embodiments, the ethanolconcentration is about at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%,40%, or greater than 40%. In specific embodiments, the ethanolconcentration is at least about 10% or more; at least about 20% or more;at least about 30% or more; or at least about 40% or more.

In some embodiments, the release rate or percent release of thetherapeutic agent is measured using an in vitro dissolution test and theabout 5% to about 40% ethanol (v/v) is present in an acidic buffer. Inspecific embodiments, the release rate or percent release of thetherapeutic agent is measured using an in vitro dissolution test whereinthe about 5% to about 40% ethanol (v/v) is present in an acidic bufferfor up to two hours. Measuring ethanol-dependent dissolution rates inthe presence of ethanol is believed to mimic ingested alcohol whichwould be present in the low pH environment of the stomach (see RubbensJ., et al., Gastric and Duodenal Ethanol Concentrations after intake ofAlcoholic Beverages in Postprandial Conditions. Molecular Pharmaceutics,(2017) 14(12), which is incorporated herein by reference in itsentirety). In specific embodiments, the percent release, or releaserate, of the therapeutic agent is measured in vitro using a standard USPharmacopeia (USP) dissolution test. For example, in certainembodiments, the test is conducted using the USP Dissolution Apparatus 2(paddle) operated at 100 RPM as in US 2012/0076865, by the steps of:

-   -   (a) Stage I: exposing the formulation to 750 mL solution of 0.1N        hydrochloric acid (HCl) (approximately pH 1.2), 37° C. for 15        minutes or 2 hours;    -   (b) Stage II: adding 250 mL of 0.316M Tris buffer (degassed and        pre-equilibrated to 37° C.) and adjusting the pH to 6.8 using        25% HCl; and exposing the formulation for 2 hours;    -   (c) drawing samples at prescribed intervals;    -   (d) filtering the sample through a suitable filter; and,    -   (e) determining the drug concentration using high performance        liquid chromatography (HPLC).    -   In further embodiments, this test is conducted in the presence        of 5-40% v/v ethanol, wherein the solution of Stage I further        comprises 5-40% v/v ethanol. E.g, if the test is conducted at 5%        (v/v), the solution of Stage I is a 750 mL solution of 0.1N HCl        and 5% v/v EtOH; if the test is conducted at 20% (v/v), the        solution of Stage I is a 750 mL solution of 0.1N HCl and 20% v/v        EtOH. In other embodiments, the test can be conducted with other        volumes of an acidic solution and/or buffer.

In some embodiments, dissolution of the pharmaceutical formulation withincreased resistance to alcohol-mediated dissolution provides animmediate release profile. In certain embodiments, dissolution of thedrug carrier core provides about 70-100% release of the therapeuticagent after about 5 to about 60 minutes of being in an aqueous bufferhaving an initial pH of about 6.8. In some embodiments, the IR drugcarrier cores release between about 70% and about 100% of thetherapeutic agent after about 5 minutes to about 60 minutes of being inan aqueous buffer having an initial pH of about 6.8. In particularembodiments, the IR drug carrier cores release between about 70-80%,70-90%, 70-100%, 80-90%, 80-100%, or 90-100% of the therapeutic agent inabout 5-10, 5-15, 5-20, 5-30, 5-45, 5-60, 10-15, 10-20, 10-30, 10-45,10-60, 15-30, 15-45, 15-60, 20-30, 20-45, 20-60, 30-45, 30-60, or 45-60minutes.

In some embodiments, dissolution of the pharmaceutical formulation withincreased resistance to alcohol-mediated dissolution provides about20-90% release of the therapeutic agent after 60 minutes of being in anon-acidic aqueous buffer having an initial pH of about 6.8. In someembodiments, dissolution of the pharmaceutical formulation withincreased resistance to alcohol-mediated dissolution in a USP IIdissolution apparatus in non-acidic aqueous buffer having initial pH ofabout 6.8 provides about 30-70% release of the therapeutic agent after60 minutes of being in the buffer phase. In certain embodiments, a twohour incubation in an acidic/fluid phase precedes incubation in thenon-acidic aqueous buffer as according to USP standards for dissolutionprofiling. Thus in some embodiments dissolution of the formulationprovides about 20-90% release of the therapeutic agent after 60 minutesof being in a non-acidic aqueous buffer having an initial pH of about6.8, wherein prior to incubation in said non-acidic aqueous buffer theformulation is incubated for two hours in an acidic solution. In certainembodiments incubation in the acidic phase is reduced to about 15minutes, or from 10-20 minutes. In some embodiments dissolution of theformulation provides about 25-80% release of the therapeutic agent after60 minutes of being in a non-acidic aqueous buffer having an initial pHof about 6.8, wherein prior to incubation in said non-acidic aqueousbuffer the formulation is incubated for 15 minutes, or about 10-20minutes, in an acidic solution. In some embodiments, dissolution offormulation in a USP II dissolution apparatus in a non-acidic aqueousbuffer having initial pH of about 6.8 provides about 30-70% release ofthe therapeutic agent after 60 minutes of being in the buffer phase,wherein prior to incubation in said buffer phase the formulation isincubated for 15 minutes or two hours in an acidic solution.

In some embodiments, the cellulose and/or polymethacrylate polymers havebeen treated with a plasticizer. A plasticizer is selected based on itsphysicochemical properties to ensure compatibility with the celluloseand/or polymethacrylate polymers. Examples of suitable plasticizersinclude, but are not limited to, acetyltributyl citrate, acetyltriethylcitrate, benzyl benzoate, dibutyl phthalate, dibutyl sebacate, diethylphthalate, dimethyl phthalate, glyceryl triacetate, polyethylene glycol(“PEG”), propylene glycol, pyrrolidone, triacetin, triethyl citrate(“TEC”) and tributyl citrate (“TBC”).

In some embodiments, the alcohol-resistant formulations provide modifiedrelease of the therapeutic agent in the absence of ethanol whilepreventing this release from accelerating in the presence of ethanol. Insome embodiments, the alcohol-resistant formulations provide modifiedrelease of the therapeutic agent in the absence of ethanol whilepreventing this release from accelerating due to the simultaneousconsumption of ethanol.

In some embodiments, the alcohol-resistant formulations provide modifiedrelease of the therapeutic agent with release kinetics that enable asingle dose be taken by the patient in a 24 hour period. In someembodiments, the alcohol-resistant formulations provide modified releaseof the therapeutic agent with release kinetics that enable a single dosebe taken by the patient in a 24 hour period and wherein release of thetherapeutic agent from said formulation is prevented from acceleratingin the presence of alcohol or due to the simultaneous consumption ofalcohol. In specific embodiments, the therapeutic agent is GHB,paracetamol, an opioid or an opiate. In other specific embodiments, thetherapeutic agent is GHB, paracetamol, codeine or oxycodone. In somespecific embodiments, the therapeutic agent is GHB.

In some embodiments, alcohol-resistant formulations are used to treat apatient suffering from a disease or condition and/or a symptom caused bya disease or condition.

In some embodiments, the alcohol-resistant formulation comprises one ormore populations of drug carrier cores comprising a therapeutic agent.In certain embodiments, the formulation comprises a core and one or morecoatings. In particular embodiments, the core comprises between 70% and90% (w/w of the core) GHB salt, 1-20% (w/w of the core) microcrystallinecellulose, and 1-10% (w/w of the core) hydroxypropylcellulose. Incertain embodiments, the formulation comprises a core and a firstcoating disposed over the core comprising ethylcellulose and methacrylicacid-ethyl acrylate co-polymer (1:1), wherein said coating is targetedto be from about 5% to about 60% by weight of the core and the ratio ofethylcellulose to co-polymer is between about 1:3 and 3:1, respectively,based on polymer weight. In preferred embodiments, the ratio ofethylcellulose to co-polymer is between about 1:2 and 2:1, respectively,based on polymer weight. In other embodiments, said formulation furthercomprises a second coating disposed over the first coating comprisingethylcellulose, methacrylic acid-ethyl acrylate co-polymer (1:1) andguar gum, wherein guar gum is added at 1-10% w/w of the cellulosepolymer, wherein said second coating is dispersed over the first coatingand targeted to be from about 1% to about 50% by weight of the core andfirst coating, and wherein the ratio of ethylcellulose to co-polymer isbetween about 1:3 and 3:1, respectively, based on polymer weight. Incertain embodiments, the ethyl cellulose in the first and/or secondcoating is Aquacoat® ECD.

In some embodiments, the alcohol-resistant formulation comprises a drugcarrier core having between 70% and 90% (w/w) GHB salt, 1-20% (w/w)microcrystalline cellulose, and 1-10% (w/w) hydroxypropylcellulose; and,a first coating comprising Aquacoat® ECD and methacrylic acid-ethylacrylate co-polymer (1:1) wherein said coating is targeted to be fromabout 5% to about 60% by weight of the core.

In some embodiments, the alcohol-resistant formulation comprises a drugcarrier core having between 70% and 90% (w/w) GHB salt, 1-20% (w/w)Avicel 101 (microcrystalline cellulose), 0-3% (w/w) L-HPC LH31(low-substituted hydroxypropyl cellulose), and 1-10% (w/w)Hydroxypropylcellulose 300-600 CPS, a first coat disposed over the corecomprising ethylcellulose (as Aquacoat® ECD) and methacrylic acid-ethylacrylate co-polymer 1:1 (as either Eudragit L30D55 or Eudragit L100-55)at a ratio of between 1:3 and 3:1 respectively, based on polymer weight;and, optionally, a top or second coat comprising ethyl cellulose,methacrylic acid-ethyl acrylate co-polymer (1:1) and guar gum which isdispersed over the first coating and targeted to be from about 1% toabout 50% by weight of the core and first coating. In certainembodiments, the ethyl cellulose in the first and/or second coating isAquacoat® ECD. In some embodiments, a sub-coat is present between thefirst coating and the core.

In certain embodiments, the GHB salt is a mixture of GHB salts. Inspecific embodiments, the GHB salt in the modified release formulationis calcium GHB monohydrate. In other embodiments, the GHB salt in theimmediate release formulation is a mixture of sodium GHB and potassiumGHB.

In some embodiments, drug carrier core comprises a mixed salt oxybate.In other embodiments, the immediate release portion of the formulationcomprises a mixed salt oxybate. This mixed salt oxybate comprisesvarying percentages of oxybate, expressed as % molar equivalents (% mol.equiv.) of Na.GHB, K.GHB, Mg.(GHB)₂, and/or Ca.(GHB)₂. The terms “%molar equivalents” and “% mol. equiv.,” as used herein, refer to molarcomposition of salts expressed as a percent of GHB equivalents. Thoseskilled in the art will understand that as each GHB unit is consideredto be one molar equivalent, the monovalent cations, Na⁺ and K⁺, have onemolar equivalent per salt, and the divalent cations, Mg⁺² and Ca⁺², havetwo molar equivalents per salt. See U.S. Pat. Nos. 8,591,922; 8,901,173;9,132,107; 9,555,017; 10,195,168 for amounts of % mol. equiv. useful inthe present disclosure.

In some embodiments, any of the salts, such as the Na.GHB salt, theK.GHB salt, the Mg.(GHB)₂ salt or the Ca.(GHB)₂, is present in about1%-5%, about 5%-10%, about 10%-15%, about 15%-20%, about 20%-25%, about25%-30%, about 30%-35%, about 35%-40%, about 40%-45%, about 45%-50%,about 50%-55%, about 55%-60%, about 60%-65%, about 65%-70%, about70%-75%, about 75%-80%, about 80%-85%, about 85%-90%, about 90%-95%, orabout 95%-100% (% mol. equiv.). In some embodiments, the Na.GHB salt ispresent in a % mol. equiv. of about 1%, about 5%, about 10%, about 15%,about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,about 85%, about 90%, about 95%, or about 100% (% mol. equiv.). In someembodiments, the Na.GHB salt is absent.

In some embodiments, where the mixed salt oxybate comprises a mixture ofNa.GHB, K.GHB, Mg.(GHB)₂, and Ca.(GHB)₂, the Na.GHB salt is present in a% mol. equiv. of about 1%-15%, 5%40%, or about 8%; the K.GHB salt ispresent in a % mol. equiv. of about 10%-30%, 15%-25%, or about 23%; theMg.(GHB)₂ salt is present in a % mol. equiv. of about 10%-30%, 15%-25%,or about 21%; and the Ca.(GHB)₂ salt is present in a % mol. equiv. ofabout 30%-60%, 40%-50, or about 48% (% mol. equiv.).

In some embodiments, the mixed salt oxybate comprises about 8% mol.equiv. of sodium oxybate, about 23% mol. equiv. of potassium oxybate,about 21% mol. equiv. of magnesium oxybate and about 48% mol. equiv. ofcalcium oxybate. In some embodiments, where the mixed salt oxybatecomprises a mixture of Na.GHB, K.GHB, Mg.(GHB)₂, and Ca.(GHB)₂, whereinthe mixture comprises Na.GHB, K.GHB, Mg.(GHB)₂, and Ca.(GHB)₂ salts arepresent in a % mol. equiv. ratio of about 8:23:21:48, respectively.

In some embodiments, where the pharmaceutical composition comprises amixture of Na.GHB, K.GHB, and Ca.(GHB)₂, the Na.GHB salt is present in a% mol. equiv. of about 5%-40%, the K.GHB salt is present in a % mol.equiv. of about 10%-40%, and the Ca.(GHB)₂ salt is present in a % mol.equiv. of about 20%-80%.

One embodiment of the present invention is a method for treating apatient who is suffering from a disease or condition, such as forexample, a disease or condition that is treatable with GHB, paracetamol,an opioid and/or an opiate. In some embodiments, the disease orcondition is treatable with GHB, paracetamol, codeine or oxycodone. Inspecific embodiments, the disease or condition is treatable with GHB. Incertain embodiments the disease or condition is a Therapeutic Categoryas described herein, such as but not limited to, sleeping disorders,drug abuse, alcohol and/or opiate withdrawal, a reduced level of growthhormone, anxiety, analgesia (including the treatment of mild, moderateand/or severe pain; including acute, chronic, breakthrough, somatic,visceral or neuropathic pain), effects in certain neurologicaldisorders, such as Parkinson's Disease, depression, certain endocrinedisturbances and tissue protection following hypoxia/anoxia such as instroke or myocardial infarction, or an increased level of intracranialpressure. Another embodiment of the invention is a method of treatingand/or preventing a symptom associated with a disease or condition suchas for example, a disease or condition treatable with GHB, including butnot limited to, excessive daytime sleepiness, cataplexy, sleepparalysis, apnea, narcolepsy sleep time disturbances, hypnagogichallucinations, sleep arousal, insomnia, essential tremor and nocturnalmyoclonus with gamma-hydroxybutyrate (GHB) or a salt thereof,comprising: orally administering to the patient in need of treatment, analcohol-resistant formulation comprising a therapeutic agent whereinthere is reduced release of the therapeutic agent in the presence ofethanol. In specific embodiments, the therapeutic agent is GHB.

One embodiment of the present invention is a method for treating apatient who is suffering from excessive daytime sleepiness, cataplexy,sleep paralysis, apnea, narcolepsy sleep time disturbances, hypnagogichallucinations, sleep arousal, insomnia, and nocturnal myoclonus withgamma-hydroxybutyrate (GHB) or a salt thereof, comprising: orallyadministering to the patient in need of treatment, a GHB formulationwith reduced GHB release in the presence of ethanol. In certainembodiments, the ethanol concentration is at least about 5%, 10%, 15%,20%, 25%, 30%, 35%, 40%, or greater than 40%. In certain embodiments,the ethanol concentration is about at least about 10% or more; at leastabout 20% or more; at least about 30% or more; or at least about 40% ormore.

Another embodiment of the invention is a method of safely administeringGHB, or a salt thereof, for treatment and/or prevention of a disease,disorder or symptom that is treatable with GHB, such as but not limitedto, sleeping disorders, drug abuse, alcohol and/or opiate withdrawal, areduced level of growth hormone, anxiety, analgesia, effects in certainneurological disorders, such as Parkinson's Disease, depression,fibromyalgia, certain endocrine disturbances and tissue protectionfollowing hypoxia/anoxia such as in stroke or myocardial infarction, oran increased level of intracranial pressure, excessive daytimesleepiness, cataplexy, sleep paralysis, apnea, narcolepsy, sleep timedisturbances (including, for example, those resulting from stress ortrauma such as post-traumatic stress disorder and/or traumatic braininjury), REM sleep behavior disorder (RBD; especially as inParkinson's), hypnagogic hallucinations, sleep arousal, insomnia(including various types of insomnia such as, for example, idiopathichypersomnia), and nocturnal myoclonus in a human patient, comprising:orally administering to the patient in need of treatment, a GHBformulation with reduced GHB release in the presence of ethanol. Incertain embodiments, the ethanol concentration is at least about 5%,10%, 15%, 20%, 25%, 30%, 35%, 40%, or greater than 40%. In certainembodiments, the ethanol concentration is about at least about 10% ormore; at least about 20% or more; at least about 30% or more; or atleast about 40% or more.

In each of the embodiments of the invention the method includesadministering GHB at between 1 and 10 grams/day or between 4.5 and 9grams/day in a 24 hour period. In some of the embodiments of theinvention the method includes administering GHB at between 7 and 10grams/day in a 24 hour period.

In a further embodiment the method can include administering GHB as asingle salt or a mixture of salts of GHB selected from the groupconsisting of a sodium salt of gamma-hydroxybutyrate (Na.GHB), apotassium salt of gamma-hydroxybutyrate (K.GHB), a magnesium salt ofgamma-hydroxybutyrate (Mg(GHB)₂), and a calcium salt ofgamma-hydroxybutyrate (Ca(GHB)₂).

Another embodiment of the present invention is a method of administeringGHB, paracetamol, an opioid or opiate (e.g. codeine or oxycodone) to apatient in need thereof, comprising administering to the patient atherapeutically effective amount of GHB, paracetamol, an opioid oropiate (e.g. codeine or oxycodone) while avoiding concomitantadministration of alcohol. A preferred embodiment is a method ofadministering GHB to a patient in need thereof, comprising administeringto the patient a therapeutically effective amount of GHB while avoidingconcomitant administration of alcohol.

The invention may also comprise a method for reducing the side effectsof GHB, paracetamol, an opioid or opiate (e.g. codeine or oxycodone) ina patient in need thereof, comprising administering to said patient aneffective amount of an alcohol rugged modified release formulation ofGHB, paracetamol, an opioid or opiate (e.g. codeine or oxycodone). Apreferred embodiment is a method for reducing the side effects of GHB ina patient in need thereof, comprising administering to said patient aneffective amount of an alcohol rugged modified release formulation ofGHB.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the in vitro dissolution profile of calciumoxybate from a delayed release (“DR”) pellet core having a polymer filmof 30% w/w of the pellet core consisting of a mixture of ethylcelluloseand poly(methacrylic acid-ethyl acrylate co-polymer). Dissolution wastested for 2 hours in acid (0.1N HCl) followed by 1 hour in Tris pH 6.8buffer.

FIG. 2 is a graph showing the dissolution rate of calcium oxybatesingle-coated pellet cores coated using two different poly(methacrylicacid-ethyl acrylate co-polymer) sources (circles and squares). Thepolymethacrylate was mixed with ethylcellulose. Also shown is thedissolution rate of calcium oxybate from a double-coated formulationwhereby the inner coat contains a mixture of ethylcellulose andmethacrylic acid-ethyl acrylate co-polymer and guar gum is incorporatedin the outer (surface) polymer coat. Calcium oxybate dissolution for thedouble-coated formulation was tested in the presence (invertedtriangles) and absence (upright triangles) of 40% ethanol in the acidphase.

FIGS. 3A and 3B are images showing the presence and absence of atransparent gel layer around the calcium oxybate pellets “DR03” in thepresence (3B) and absence (3A) of ethanol, respectively. The gel layerformation shown in the presence of ethanol is for calcium oxybatepellets having a double polymer film coat, whereby the inner coatcontains a mixture of ethylcellulose and methacrylic acid-ethyl acrylateco-polymer and guar gum is incorporated in the outer (surface) polymercoat.

FIG. 4 is a graph showing the in vitro dissolution release profile ofcoated Calcium oxybate (GHB) pellets in Tris (pH 6.8) buffer following15 minute pre-exposure to 0.1N HCl containing 0%, 10%, 20% or 40% v/vethanol.

FIG. 5A is an image showing the variation in the shear storage modulus(elastic response, G′) measured at a probe frequency sweep of 1 Hz overtime following exposure of polymer coated placebo (sucrose) pellet cores(coated with a binary polymer mix of ethylcellulose & methacrylicacid-ethyl acrylate co-polymer (at a ratio (% w/w dry polymer) of 1:2)to 40% v/v EtOH in 0.1N HCl buffer.

FIG. 5B shows the variation in the shear storage modulus (elasticresponse, G′) measured at a probe frequency sweep of 1 Hz over timefollowing transfer of polymer coated placebo (sucrose) pellet cores(coated with a binary polymer mix of ethylcellulose & methacrylicacid-ethyl acrylate co-polymer (at a ratio (% w/w dry polymer) of 1:2)from 0.1N HCl buffer containing 40% v/v EtOH to Tris pH 6.8 buffer (noEtOH).

FIG. 6 is a graph showing the in vitro dissolution profile for GHBformulations both with (squares) and without (closed circles) anadditional outer polymer film coat consisting ofEC/L100-55/GG/polyvinylpyrrolidone (“PVP”) when tested for 2 hours inacid (0.1N HCl) followed by 1 hour in Tris pH 6.8 buffer. Also shown isthe dissolution of the double-coated GHB formulation when exposed to 40%v/v EtOH/acid buffer for 2 hours followed by 1 hour exposure to Tris pH6.8 buffer without EtOH.

FIG. 7 is a graph comparing the in vitro dissolution profile for GHBformulations in either Tris or bicarbonate buffer post exposure to HCLbuffers and in either the presence or absence of 20% v/v ethanol.

FIG. 8 is a graph showing the impact of the use of a polymer sub-coat onthe resultant dissolution profile of binary polymer film coated calciumoxybate pellets exposed for 1-2 hours to 0.1N HCl buffer followed by 1hour in Tris pH 6.8 buffer both with (circles) and without the sub-coat(inverted triangles) as well as after exposure to 0.1N HCl buffercontaining 20% v/v ethanol for 15 minutes followed by 1 hour exposure toTris pH 6.8 buffer, both with (squares) and without the sub-coat(diamonds).

FIG. 9 is a graph showing a sustained release (close to first order)oxybate dissolution profile over a 4 hour period under bi-phasicdissolution test conditions following application of a binary polymerfilm of ethylcellulose (EC) and methacrylic acid-ethylacrylateco-polymer 1:1 (as Eudragit® L100-55) to calcium oxybate pellets. Thebinary polymer film was prepared as a solution in organic solvent.

FIG. 10 is a graph showing hydroxybutyrate dissolution profile followingapplication of a binary polymer film of ethylcellulose (EC) andmethacrylic acid-methyl methacrylate co-polymer 1:1 (as Eudragit® L100)prepared as an aqueous dispersion and applied to calcium3-hydroybutyrate (Ca-3HB) pellets. The binary polymer film was applieddirectly to Ca3HB pellets to a level equivalent to 15% w/w of the pelletcore.

FIG. 11 is a graph showing hydroxybutyrate dissolution profile followingapplication of a binary polymer film of ethylcellulose (EC) andmethacrylic acid-methyl methacrylate co-polymer 1:2 (as Eudragit® S100)prepared as an aqueous dispersion and applied to calcium3-hydroybutyrate (Ca-3HB) pellets. The binary polymer film was applieddirectly to Ca3HB pellets to a level equivalent to 15% w/w of the pelletcore. The incorporation of the Eudragit® S100 polymer with pH 7dissolution trigger point results in complete suppression ofhydroxybutyrate release in acid (120 min), followed by extendedsuppression of release over 2.5 hours in Tris pH 7.5 buffer, above thepH dissolution trigger of S100 polymer over a 5 hour period. After 5hours exposure to Tris pH 7.5 buffer only approximately 20%hydroxybutyrate is released from the coated pellet core.

FIG. 12 is a graph showing oxybate dissolution profile from calciumoxybate pellets following application of a binary ethylcellulose (asEthocel™ 20) and methacrylic acid-methyl methacrylate co-polymer 1:1 (asEudragit® L100), at a % w/w dry polymer ratio of 1:2 respectively,(closed circles). The figure also shows oxybate release from the binaryfilm coated pellets following 15 minute exposure to 20% v/v EtOH in 0.1NHCl (dashed line, triangles) and 40% v/v EtOH in 0.1N HCl (dashed line,inverted triangle) followed by release in Tris pH 6.8 buffer. Thedissolution profile following the application of a second binary polymerfilm consisting of ethylcellulose (as the 30% aqueous dispersion) andmethacrylic acid-ethylacrylate 1:1 co-polymer (as Eudragit L30D-55) isshown, (closed squares). The oxybate dissolution profile in Tris (pH6.8) buffer following 15 minute pre-exposure to 0.1N HCl containing 0%,10%, 20% or 40% v/v ethanol is also shown for the formulation withtopcoat applied.

FIG. 13 is a graph showing paracetamol release following application ofa binary polymer film coat consisting ethylcellulose (as 30% aqueousdispersion, Aquacoat® ECD) and methacrylic acid-ethylacrylate 1:1co-polymer (as Eudragit® L30D-55). The effect of increasing polymer filmthickness on resultant dissolution rate is demonstrated. The figure alsoshows the impact of 15 minute pre-exposure to 40% v/v EtOH in 0.1N HClon subsequent release in Tris pH 6.8 buffer.

FIG. 14 is a graph comparing the dissolution of two sustained release(SR) oxybate prototypes prepared for human pharmacokinetic studies. The‘SR1’ consists of a calcium oxybate (monohydrate) pellet core onto whichan ethylcellulose-based functional film coat is applied. The ‘SR2’consists of the same pellet core onto which a binary polymer film isapplied consisting of a 1:1 mix, based on dry polymer weight, ofethylcellulose and methacrylic acid ethylacrylate (1:1) co-polymer.

FIG. 15 is a graph comparing the dissolution of a prototype, SR2′, underdifferent pH conditions. The prototype consists of consists of a calciumoxybate (monohydrate) pellet core onto which a binary polymer film isapplied consisting of a 1:1 mix, based on dry polymer weight, ofethylcellulose and methacrylic acid ethylacrylate (1:1) co-polymer.

FIG. 16 is a graph comparing the human pharmacokinetic profiles of twoSR oxybate prototypes administered to healthy volunteers two hours afterthe start of a high-fat, high-calorie breakfast. A total dose equivalentto 4.5 g sodium oxybate was administered. The ‘SR1’ consists of acalcium oxybate (monohydrate) pellet core onto which anethylcellulose-based functional film coat is applied. The ‘SR1’prototype was administered individually. The ‘SR2’ consists of the samepellet core onto which a binary polymer film is applied consisting of a1:1 mix, based on dry polymer weight, of ethylcellulose and methacrylicacid ethylacrylate (1:1) co-polymer. The ‘SR2’ prototype wasadministered in combination with an aqueous oxybate solution at a doseratio of 1:2.5 solution to ‘SR2’ respectively.

FIG. 17 is a graph comparing the dissolution in Tris pH 6.8 buffer of abinary film prototype of Example 9, ‘SR2’, in the absence (circles) orpresence (triangles) of a 15 minute pre-exposure to 0.1N HCl containing20% v/v ethanol. Comparison is made to the dissolution of the ‘SR1’prototype of Example 9 in Tris pH 6.8 buffer.

FIG. 18 is a graph comparing the dissolution of two delayed release (DR)oxybate prototypes prepared for human pharmacokinetic studies. The ‘DR1’consists of a calcium oxybate (monohydrate) pellet core onto which amethacrylic acid-ethyl acrylate based functional film coat is applied.The ‘SR2’ consists of the same pellet core onto which a binary polymerfilm is applied consisting of a mix of ethylcellulose and methacrylicacid ethylacrylate (1:1) co-polymer. A guar gum containing ‘top-coat’ isalso applied to ‘DR2’.

FIG. 19 is a graph comparing the dissolution of a prototype, ‘DR2’,under different pH conditions. The prototype consists of a calciumoxybate (monohydrate) pellet core onto which a binary polymer film isapplied consisting of a mix of ethylcellulose and methacrylic acidethylacrylate (1:1) co-polymer. A guar gum containing ‘top-coat’ is alsoapplied.

FIG. 20A is a graph comparing the human pharmacokinetic profiles of twoDR oxybate prototypes administered to healthy volunteers two hours afterthe start of a high-fat, high-calorie breakfast. The ‘DR1’ consists of acalcium oxybate (monohydrate) pellet core onto which a methacrylicacid-ethylacrylate functional film coat is applied. The ‘DR2’ consistsof the same pellet core onto which a binary polymer film is appliedconsisting of a mix of ethylcellulose and methacrylic acid ethylacrylate(1:1) co-polymer. A guar gum containing ‘top-coat’ is also applied to‘DR2’.

FIG. 20B is a graph of the human pharmacokinetic profiles of themodified release ‘DR2’ particle in combination with an oxybate solution(a mixture of sodium and potassium oxybate salts) administered at 4.5 g,7 g and 9 g dose equivalent to the sodium oxybate salt. The compositionswere administered two hours after the start of a high-fat, high caloriebreakfast.

FIG. 21A is a graph comparing the dissolution in Tris pH 6.8 buffer of abinary film prototype of Example 10, ‘DR2’, in the absence (circles) orpresence (triangles) of a 15 minute pre-exposure to 0.1N HCl containing20% v/v ethanol (note: only the modified release component having theinner and outer binary polymer film coatings was tested).

FIG. 21B is a graph presenting the dissolution of a binary polymer filmprototype of Example 10, ‘DR2’, in the presence and absence of EtOH forup to 2 hours in the acid phase, (note: only the modified releasecomponent having the inner and outer binary polymer film coatings wastested). The effect of 2 hours EtOH exposure on subsequent oxybaterelease rate in Tris pH 6.8 buffer is shown.

FIG. 22 is a graph showing the in vitro dissolution profile of codeinephosphate from a pellet core when prepared with a binary film coatingand when dissolution was tested for 45 minutes in Tris pH 6.8 buffer.

FIG. 23 is a graph showing the impact of polymer film coating thicknesson the in vitro dissolution profile of codeine phosphate from a pelletcore using three different thicknesses, equivalent to 15% w/w polymer,22% w/w polymer and 30% w/w polymer of the uncoated codeine phosphatepellet core, dissolution was tested for 15 minutes in acid (0.1N HCl)followed by between 90 to 120 minutes in Tris pH 6.8 buffer and testedin the presence and absence of 20% v/v and 40% v/v ethanol in the 15minute acid phase.

FIG. 24 is a graph showing the impact of polymer film coating thicknesson the in vitro dissolution profile of codeine phosphate from a pelletcore following the application of a polymer film coat consisting of a1:1 mixture of ethylcellulose and poly(methacrylic acid-ethyl acrylateco-polymer using three different thicknesses, equivalent to 15% w/wpolymer, 22% w/w polymer and 30% w/w polymer of the uncoated codeinephosphate pellet core, dissolution was tested for 60 minutes exposure ofthe composition to 20% v/v EtOH in acid (0.1 N HCl), with impact of EtOHexposure on in vitro dissolution rate in neutral pH buffer discerned bysubsequently testing the composition in Tris pH 6.8 buffer.

FIG. 25 is a graph showing the two-phase in vitro dissolution profilesof codeine phosphate from a pellet core having a binary polymer filmcoat of 22% w/w of the uncoated pellet core.

FIG. 26 is a graph showing the two-phase in vitro dissolution profilesof codeine phosphate from a pellet core prepared as per Example 11. Thein vitro dissolution characteristics of ‘single’ and ‘double’ coatedcodeine phosphate pellets were determined. The ‘single coated’ pelletswere prepared by applying a polymer film coat consisting of a 1:1mixture of ethylcellulose and poly(methacrylic acid-ethyl acrylateco-polymer). The binary polymer film coat was applied to a target weightgain of 30% w/w polymer of the uncoated codeine phosphate pellet core.The ‘double coated’ pellets were prepared by adding an additional outerpolymer film coat consisting of a mixture of ethylcellulose,poly(methacrylic acid-ethyl acrylate co-polymer) and guar gum. Bothcompositions were exposed to 0% v/v, 20% v/v and 40% v/v EtOH for up to60 minutes during the acid phase dissolution test.

FIG. 27 is a graph showing the in vitro dissolution of codeine phosphatetablets in Tris pH 6.8 buffer.

FIG. 28 is a graph showing the impact of the thickness of the binarypolymer film coating on the dissolution of codeine phosphate tablets inthe presence and absence of ethanol.

FIG. 29 is a graph showing the in vitro dissolution of oxycodonehydrochloride pellets in Tris pH 6.8 buffer.

FIG. 30 is a graph showing the impact of the thickness of the binarypolymer film coating on the dissolution of oxycodone hydrochloridepellets in the presence and absence of ethanol.

FIG. 31 is a graph showing the in vitro dissolution of oxycodonehydrochloride pellets using either single or double-coated pellets.

FIG. 32 is a graph showing the in vitro dissolution of oxycodonehydrochloride tablets in Tris pH 6.8 buffer.

FIG. 33 is a graph showing the impact of the thickness of the binarypolymer film coating on the dissolution of oxycodone hydrochloridetablets in the presence and absence of ethanol.

DETAILED DESCRIPTION OF THE INVENTION

Alcohol-induced dose dumping is a critical parameter to consider whendesigning and developing modified release oral formulations. Oralformulations usually contain high concentrations of drug. Some modifiedrelease oral dosage forms can contain drugs or excipients that havealtered solubility in ethanol. Ingestion of alcohol, eitherintentionally or unintentionally, may lead to dangerously high drugexposure if the modified release formulation is sensitive to ethanolconcentration. Thus provided herein are alcohol rugged oral formulationsthat are resistant to dose dumping and which provide improveddissolution properties in increasing concentrations of ethanol.

In the following description, reference is made to the accompanyingdrawings that form a part hereof, and in which is shown by way ofillustration specific embodiments in which the invention may bepracticed. These embodiments are described in sufficient detail toenable those skilled in the art to practice the invention, and it is tobe understood that other embodiments may be utilized and thatstructural, logical and electrical changes may be made without departingfrom the scope of the present invention. The following description is,therefore, not to be taken in a limited sense, and the scope of thepresent invention is defined by the appended claims.

The following patents and applications are hereby incorporated byreference in their entireties for all purposes: U.S. Pat. Nos.6,472,431, 6,780,889, 7,262,219, 7,851,506, 8,263,650, 8,324,275;8,859,619, 8,952,062, 8,591,922, 8,771,735, 7,895,059; 7,797,171;7,668,730; 7,765,106; 7,765,107, 8,457,988, 8,589,182, 8,731,963;8,771,735, 8,772,306, 8,778,398, 9,795,567, U.S. Pat. Application Nos.61/317,212, 13/071,369, 14/045,673, 14/172,751, 14/821,384, 15/385,447,PCT/US2010/033572, PCT/US2009/061312, 2009/0137565; and 2012/0076865.The following patents are also incorporated by reference: U.S. Pat. Nos.5,380,937; 4,393,236 German Patent DD 237,309 A1; and British Pat. Nos.2295390 and 922,029. In addition, these patents are also incorporated byreference: U.S. Pat. Nos. 4,524,217, 6,316,025, 7,993,673, 8,216,610,9,271,974.

The following patents and applications are also incorporated byreference for all purposes: US Publication No. 2006/0193912 describescompositions with a mixture of gums and ionizable gel strength enhancingagent that are expected to exhibit reduced alcohol induced dose dumping;US Publication No. 2007/0264346 provides an oral pharmaceutical formcomprising micromultiparticles of the reservoir type for the modifiedrelease of at least one active principle, said form being resistant toimmediate dumping of the dose of active principle in the presence ofalcohol; International (PCT) Publication No. 2007/053698 describesonce-a-day controlled release compositions of opioid analgesics thatexhibit improved properties with respect to co-administration withaqueous alcohol; International (PCT) Publication No. 2008/086804describes use of polyglycol, especially, polyethylene glycol for thepreparation of a pharmaceutical composition, wherein the composition iswithout ethanol induced dose dumping. According to the application, theoral solid dosage forms are prepared by heating in order to melt orsoften the polymer followed by solidification; US Publication No.2008/0085304 describes ethanol-resistant controlled releasepharmaceutical compositions comprising a hydrophilic gum, ahomopolysaccharide gum, and a pharmaceutical diluent; and, USPublication No. 2009/0155357 discloses a modified release oral dosageform comprising alcohol insoluble coating, which is preferably waterinsoluble. Other patent or non-patent references cited throughout arealso incorporated by reference in their entireties.

Definitions

In the specification and claims that follow, references will be made toa number of terms which shall be defined to have the following meaning.

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item. Theterm “or” means “and/or”. The terms “comprising”, “having”, “including”,and “containing” are to be construed as open-ended terms (i.e., meaning“including, but not limited to”).

“Alcohol induced dose dumping” means the increased release of a drugfrom a dosage form in the presence of alcohol.

“Acidic aqueous buffer” or “acid buffer” means a buffer with pH<5.

“Alcohol rugged” or “alcohol resistant” means a formulation that isresistant to alcohol induced dose dumping, such that the rate of drugrelease from the formulation does not significantly increase, or islowered, in the presence of alcohol.

“Alcohol” as used herein refers to ethanol, any ethanol containingproduct, or an ethanol-containing (“alcoholic”) beverage such as beer,wine, and hard liquors such as vodka, rum, or whiskey;ethanol-containing beverage is commonly referred to as an alcoholicbeverage, liquor, or simply alcohol all of which are included herein asreferring to “alcohol” or “ethanol”. It is meant to include any ethanolcontaining product or excipient such as liquid media or solid dosageforms (tablets, capsules for example), including those listed by the FDAInactive Ingredient Database (IID) as alcohol-containing excipients suchas, for example, alcohol used in oral therapeutic solutions, benzylalcohol (used in capsule and soft gelatin caps and DR or SR tablets),butyl alcohol, cetyl alcohol, cetostearyl alcohol, isopropyl alcohol andstearyl alcohol.

“Co-ingested” or “co-ingestion” means the presence of both a drug (e.g.GHB) and alcohol in the body (e.g. stomach) which occurred througheither simultaneous or subsequent ingestion of each and includesco-ingestion that occurs either intentionally or accidentally.

“Controlled release” or “CR” dosage forms or formulations as used hereinare meant to include any dosage form or formulation maintains drugrelease over a sustained period at a nearly constant rate.

“Daily dose” means the total dose or dosage that is taken within a 24hour period.

“Drug carrier core” or “drug containing core” or “core” means the innermaterial which contains the drug as well as any suitable excipients, ifnecessary, used to prepare or maintain the drug inside the core such asbinders or lubricants. The drug carrier core can be prepared in the formof numerous shapes and/or sizes including, for example, granules,tablets, spheres, pellets, minitablets, microtablets, microparticles,microspheres, microcapsules, micropellets, beads, multi-particulates aswell as particles having diameters up to about 5 mm; the drug carriercores may be any suitable particle size or shape. For example, the drugcarrier cores can be in the form of a “micropellets” having a particlesize range of about 50-5,000 μm, or can be in the form of “minitablets”which have a nominal (e.g., mean) particle diameter in the range ofabout 2-5 mm. The drug carrier cores can be “microtablets” which havenominal (e.g., mean) particle diameters of less than about 2 mm, forexample about 1-2 mm. The drug carrier cores can also be microspheres,having a particle size range of about 50-500 μm. The drug carrier corescan be sized prior to coating, or after coating with one or moresub-coats, coatings, or top-coats. For example the drug carrier corescan be sized by screening or sieving prior to coating. Exemplary sizeranges include, but are not limited to about 0.5 mm to 0.8 mm, 0.5 mm to1.0 mm, 0.5 mm to 1.25 mm, 0.5 to 1.5 mm, 0.5 to 1.75 mm, 0.5 to 2.0 mm,0.8 mm to 1.0 mm, 0.8 mm to 1.25 mm, 0.8 to 1.5 mm, 0.8 to 1.75 mm, 0.8to 2.0 mm-1.0 mm to 1.25 mm, 1.0 to 1.5 mm, 1.0 to 1.75 mm, 1.0 to 2.0mm, 1.25 to 1.5 mm, 1.25 to 1.75 mm, 1.25 to 2.0 mm, 1.5 to 1.75 mm, 1.5to 2.0 mm, or 1.75 to 2.0 mm Further, the drug carrier core can also bereferred to a core relating to its size and/or shape; for example, a“drug carrier core” can be referred to as a “pellet core” when the drugcarrier core is the size and/or shape of a pellet, or the drug carriercore can also be referred to as a “bead core” when the drug carrier coreis the size and/or shape of a bead. For example, a “calcium oxybatepellet core” is meant to be a “drug carrier core” which comprisescalcium oxybate and which is the size and/or shape of a pellet;similarly; a “calcium 3-hydroybutyrate (Ca-3HB) pellet core” or “Ca3HBpellet core” is meant to is meant to be a “drug carrier core” whichcomprises calcium 3-hydroybutyrate and which is the size and/or shape ofa pellet.

“Ethanol rugged” “ethanol resistant”, “alcohol rugged”, or “alcoholresistant” means a formulation that is resistant to alcohol induced dosedumping, such that the rate of drug release from the formulation doesnot significantly increase, or is lowered, in the presence of ethanol;comparison of the drug release rate can be measured using the F2similarity test as described in Shah, V P et al., In vitro DissolutionProfile Comparison—Statistics and Analysis of the Similarity Factor, f2.Pharm Research, (1998) 15 (6).

“EtOH” means ethanol.

“Nightly dose” means the total dose or dosage that is taken within a 24hour period but usually taken before or during someone's sleep cycle.

“Dosage amount” means an amount of a drug suitable to be taken during afixed period, usually during one day (i.e., daily or nightly or within a24 hour period).

“Dosage amount adapted for oral administration” means a dosage amountthat is of an amount deemed safe and effective for the particularpatient under the conditions specified. As used herein and in theclaims, this dosage amount is determined by following therecommendations of the drug manufacturer's Prescribing Information asapproved by the US Food and Drug Administration.

“Dosage form” means a drug formulation which may be prescribed and/oradministered to a subject and is meant to include any solid, semi-solid,liquid, suspension, frozen or freeze-dried preparation of a drug,including but not limited to, tablets, minitablets, soft or hardcapsules, gel capsules, caplets, granules, pellets, micropellets, beads,powders, sachets, liquids, suspensions and the like.

“Dosing regimen” means the dose of a drug taken at a first time by apatient and the interval (time or symptomatic) and dosage amounts atwhich any subsequent doses of the drug are taken by the patient. Eachdose may be of the same or a different dosage amount.

A “dose” means the measured quantity of a drug to be taken at one timeby a patient.

“Delayed release” or “DR” refers to dosage forms that delay the releaseof the active agent until the dosage form has passed through the stomachafter oral administration; such as for example, delaying release of theagent such that not more than about 0% to 40% is released within about 1hour to about 2 hours of being in an acidic aqueous environment (pH<5).

“Immediate release” or “IR” refers to dosage forms that are formulatedto release an active drug immediately after oral administration; nodeliberate effort is made to modify the drug release rate in immediaterelease dosage forms or formulations. Immediate-release productsgenerally result in relatively rapid drug absorption and onset ofaccompanying pharmacodynamic effects. Immediate release dosage formscomprising a therapeutic agent include those, for example, that releaseabout 70% to about 100% of the therapeutic agent after about 5 minutesto about 60 minutes of being ingested, or in an aqueous buffer.

“Methacrylates” refers to derivatives of methacrylic acid.

“Modified release” or “MR” dosage forms refers to a mechanism that (incontrast to immediate-release dosage forms) delivers a drug with a delayafter its administration (delayed-release dosage or “DR”) or for aprolonged period of time including suspended release (“SR”) as outlinedbelow and extended-release (“ER”, “XR”, “XL”) dosages or to a specifictarget in the body (targeted-release dosage); it is meant to include anydosage form or formulation which is not an immediate release dosage formor formulation including those described in Chapter 17 of “AppliedBiopharmaceutics and Pharmacokinetics”, Sixth Edition; Shargel et al.,which is incorporated herein by reference; thus for the purposes herein,MR also includes “sustained release” or “SR” dosage forms and “extendedrelease” or “ER” dosage forms and “delayed release” or “DR” dosageforms.

“Non-acidic aqueous solution” or “non-acidic aqueous buffer” means asolution or buffer with pH>5.

A “patient” means a human in need of medical treatment. In oneembodiment medical treatment can include treatment of an existingcondition, such as a disease or disorder, prophylactic or preventativetreatment, or diagnostic treatment. In another embodiment, medicaltreatment also includes administration to treat “therapeutic categories,including excessive daytime sleepiness, cataplexy, sleep paralysis,apnea, narcolepsy, sleep time disturbances, hypnagogic hallucinations,sleep arousal, insomnia, and nocturnal myoclonus.

“Paracetamol” also known as “N-acetyl-p-aminophenol”, “acetaminophen”and/or “APAP”, is an analgesic and antipyretic agent and is widely usedin prescription and non-prescription medicines.

“Polymethacrylate” or “Poly(methacrylic acid)” or “PMAA” means a polymermade from methacrylic acid.

“Providing” means giving, administering, selling, distributing,transferring (for profit or not), manufacturing, compounding, ordispensing.

“Side effect” means a secondary effect resulting from taking a drug. Thesecondary effect can be a negative (unfavorable) effect (i.e., anadverse side effect) or a positive (favorable) effect.

“Sustained release” or “SR” refers to dosage forms designed to release(liberate) a drug at a predetermined rate in order to maintain aconstant drug concentration for a specific period of time with minimumside effects.

Pharmacokinetic parameters referred to herein describe the in vivocharacteristics of drug (or a metabolite or a surrogate marker for thedrug) over time. These include plasma concentration (C), as well asC_(max), C_(n), C₂₄, T_(max), AUC_(0-t) and AUC_(0-inf).

The term “T_(max)” refers to the time from drug administration untilC_(max) is reached. “AUC” is the area under the curve of a graph of themeasured plasma concentration of an active agent vs. time, measured fromone time point to another time point. For example AUC.sub.0-t is thearea under the curve of plasma concentration versus time from time 0 totime t, where time 0 is the time of initial administration of the drug.Time t can be the last time point with measurable plasma concentrationfor an individual formulation. The AUC_(0-∞). or AUG_(0-INF) is thecalculated area under the curve of plasma concentration versus time fromtime 0 to time infinity. In steady-state studies, AUC_(0-τ) is the areaunder the curve of plasma concentration over the dosing interval (i.e.,from time 0 to time τ (tau), where tau is the length of the dosinginterval.

It may be advantageous to incorporate a pharmacy management system intothe method of the present invention. “Pharmacy management systems” arecomputer-based systems that are used by commercial pharmacies to manageprescriptions and to provide pharmacy and medical personnel withwarnings and guidance regarding drugs being administered to patients.Such systems typically provide alerts warning either or both of healthcare providers and patients when a drug that may be harmful to theparticular patient is prescribed. For example, such systems can providealerts warning that a patient has an allergy to a prescribed drug, or isreceiving concomitant administration of a drug that can have a dangerousinteraction with a prescribed drug. In some cases it may provide awarning to a patient who is known or suspected of abusing alcohol whenadministration of the drug with alcohol is potentially dangerous. U.S.Pat. Nos. 7,895,059; 7,797,171; 7,668,730; 7,765,106; 7,765,107;5,758,095, 5,833,599, 5,845,255, 6,014,631, 6,067,524, 6,112,182,6,317,719, 6,356,873, 7,072,840, and 8,731,963 each of which isincorporated herein by reference, disclose various pharmacy managementsystems and aspects thereof. Example pharmacy management systems are nowcommercially available, e.g., CENTRICITY Pharmacy from BDM InformationSystems Ltd., General Electric Healthcare, Waukesha, Wis., Rx30 PharmacySystems from Transaction Data Systems, Inc., Ocoee, Fla., SPEED SCRIPTfrom Digital Simplistics, Inc., Lenexa, Kans., and various pharmacymanagement systems from OPUS-ISM, Hauppauge, N.Y.

In some embodiments, a pharmacy management system may be required orpreferred as part of a drug distribution program. For example, thepresent invention includes a method for distributing a drug containingGHB or a salt thereof to an approved pharmacy, the method comprising:(1) Identifying an approved pharmacy that has an established managementsystem to dispense information concerning the risks associated withingesting alcohol concomitantly to said drug to patients that areprescribed said drug; (2) Providing said pharmacy with said informationrelated to the risks; and (3) Authorizing distribution of said drug tosaid pharmacy, wherein said pharmacy dispenses the drug with saidinformation when filling a prescription for said drug. The establishedmanagement system may include an electronic alert to employees todispense said information with said drug when prescriptions are filled.Such information may be dispensed in written form, for example in abrochure explaining the risks of concomitant ingestion of GHB andalcohol. For example, the information dispensed with GHB may advise apatient of the potential for enhanced potency of GHB if the patient alsoco-ingests alcohol. Alternatively, or in addition thereto, theinformation dispensed with GHB may advise a patient of the potential fordecreased potency of GHB if the patient also co-ingests alcohol. Suchinformation may also be dispensed in verbal form. Distributors maymaintain a directory of approved pharmacies, for example in a computerreadable storage medium, to further ensure that GHB is dispensed only topatients who are advised of the additive effects.

In addition, the system can prevent the dispensing of GHB or saltthereof until proper testing or confirmation is obtained that thepatient is not taking or going to take large amounts of alcoholconcomitantly with GHB, as may be expected with some who suffers fromalcoholism. Alternatively, the patient can be warned of the adverseeffect and instructed to modify or skip the dose of GHB to accommodatethe increased or reduced effects of GHB due to alcohol use.

A pharmacy management system of the present invention can be a REMSsystem as shown in U.S. Pat. Nos. 7,895,059; 7,797,171; 7,668,730 and8,731,963. Warnings may be administered through the existing pharmacymanagement system as described in the patents above.

Therapeutic Agents

There are a number of therapeutic agents that can be used withalcohol-resistant formulations of the invention, including thoseapproved drugs already cited by the FDA as requiring a test for alcoholinduced dose dumping. In addition, products which are part of an ANDAapplication and requiring a test for alcohol induced dose dumping arealso included. In response to the FDA's concerns about the safety issueof alcohol induced dose dumping, the Division of Bioequivalence (DBE),in the Office of Generic Drugs, Center for Drug Evaluation and Research,US-FDA adopted a policy of requesting information on in vitro dosedumping in the presence of alcohol in its review of ANDA applicationsfor certain classes of modified release (MR) or modified release drugproducts, for example all MR opioid products. The DBE's current policyis to request that ANDA applicants perform an in vitro dose dumping inalcohol test on a particular generic product if the approval package forthe corresponding RLD shows that in vitro dose dumping in alcohol testresults were requested by the agency for the New Drug Application (NDA)for the product. The drug products for which the DBE requests the invitro dose dumping in alcohol test can be located in FDA's Guidance forIndustry, Individual Products Bioequivalence Recommendations Guidances,and all of which may be considered for use in alcohol resistantformulations of the invention. In addition, the National Institute ofHealth (NIH) Publication No. 13-5329 (Published 2003; Revised 2014 andincorporated herein by reference) from the National Institute on Alcoholand Alcoholism discusses “Harmful Interactions Mixing Alcohol withMedicines” and lists a number of drugs which are contraindicated withalcohol and all of which may be considered for use with alcoholresistant formulations of the invention.

In some embodiments the therapeutic agent is present as a prodrug ordrug conjugate. In one embodiment, a drug for use in the invention is anopioid or an opiate. In some embodiments, a drug for use in theinvention is selected from morphine, hydrocodone, oxycodone, fentanyl,sufentanyl, codeine, tapentadol, tramadol, meperidine,3,4-Methylenedioxymethamphetamine, paracetamol, codeine, oxycodone andGHB. In specific embodiments, a drug for use in the invention is GHB.

Gamma Hydroxybutyrate (GHB)

GHB (also called oxysorbate or oxybate) is approved in the United States(US) for the treatment of excessive daytime sleepiness (EDS) and for thetreatment of cataplexy, both in patients with narcolepsy. GHB iscommercially sold as Xyrem® sodium oxybate by Jazz Pharmaceuticals.“GHB”, oxybate, a GHB salt or Xyrem® will be used to refer to theseactive forms. In some embodiments, GHB can exist as individual sodium,calcium, potassium, or magnesium salts and can also exist as a mixtureof two or more of these salts. See U.S. Pat. No. 8,591,922 which isincorporated herein by reference in its entirety.

In certain embodiments, the mixed salt oxybate comprises varyingpercentages of oxybate, expressed as % molar equivalents (% mol. equiv.)of Na.GHB, K.GHB, Mg.(GHB)₂, and/or Ca.(GHB)₂. The terms “% molarequivalents” and “% mol. equiv.,” as used herein, refer to molarcomposition of salts expressed as a percent of GHB equivalents. Thoseskilled in the art will understand that as each GHB unit is consideredto be one molar equivalent, the monovalent cations, Na⁺ and IC⁺, haveone molar equivalent per salt, and the divalent cations, Mg⁺² and Ca⁺²,have two molar equivalents per salt. See U.S. Pat. Nos. 8,591,922;8,901,173; 9,132,107; 9,555,017; 10,195,168 for amounts of % mol. equiv.useful in the present disclosure.

In some embodiments, any of the salts, such as the Na.GHB salt, theK.GHB salt, the Mg.(GHB)₂ salt or the Ca.(GHB)₂, is present in about1%-5%, about 5%-10%, about 10%-15%, about 15%-20%, about 20%-25%, about25%-30%, about 30%-35%, about 35%-40%, about 40%-45%, about 45%-50%,about 50%-55%, about 55%-60%, about 60%-65%, about 65%-70%, about70%-75%, about 75%-80%, about 80%-85%, about 85%-90%, about 90%-95%, orabout 95%-100% (% mol. equiv.). In some embodiments, the Na.GHB salt ispresent in a % mol. equiv. of about 1%, about 5%, about 10%, about 15%,about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,about 85%, about 90%, about 95%, or about 100% (% mol. equiv.). In someembodiments, the Na.GHB salt is absent.

In some embodiments, where the mixed salt oxybate comprises a mixture ofNa.GHB, K.GHB, Mg.(GHB)₂, and Ca.(GHB)₂, the Na.GHB salt is present in a% mol. equiv. of about 1%-15%, 5%-10%, or about 8%; the K.GHB salt ispresent in a % mol. equiv. of about 10%-30%, 15%-25%, or about 23%; theMg.(GHB)₂ salt is present in a % mol. equiv. of about 10%-30%, 15%-25%,or about 21%; and the Ca.(GHB)₂ salt is present in a % mol. equiv. ofabout 30%-60%, 40%-50, or about 48% (% mol. equiv.).

In some embodiments, the mixed salt oxybate comprises about 8% mol.equiv. of sodium oxybate, about 23% mol. equiv. of potassium oxybate,about 21% mol. equiv. of magnesium oxybate and about 48% mol. equiv. ofcalcium oxybate. In some embodiments, where the mixed salt oxybatecomprises a mixture of Na.GHB, K.GHB, Mg.(GHB)₂, and Ca.(GHB)₂, whereinthe mixture comprises Na.GHB, K.GHB, Mg.(GHB)₂, and Ca.(GHB)₂ salts arepresent in a % mol. equiv. ratio of about 8:23:21:48, respectively.

In some embodiments, where the pharmaceutical composition comprises amixture of Na.GHB, K.GHB, and Ca.(GHB)₂, the Na.GHB salt is present in a% mol. equiv. of about 5%-40%, the K.GHB salt is present in a % mol.equiv. of about 10%-40%, and the Ca.(GHB)₂ salt is present in a % mol.equiv. of about 20%-80%.

Methods of making individual and mixed GHB salts are described, forexample, in U.S. Pat. Nos. 4,393,236, and 8,591,922 which areincorporated herein by reference.

GHB treatment substantially reduces the signs and symptoms ofnarcolepsy, i.e. excessive daytime sleepiness, cataplexy, sleepparalysis, apnea, narcolepsy, sleep time disturbances, hypnagogichallucinations, sleep arousal, insomnia, and nocturnal myoclonus. Inaddition, GHB increases total sleep time and REM sleep, and it decreasesREM latency (Mamelak et al, 1973; Yamada et al., 1967; Bedard et al.,1989), reduces sleep apnea (Scrima et al., 1987), and improves generalanesthesia (Hasenbos and Gielen, 1985).

GHB has several clinical applications other than narcolepsy and sleepdisorders. GHB has been reported to reduce alcohol craving, the numberof daily drinks consumed, and the symptoms of alcohol withdrawal inpatients (Gallimberti et al., 1989; Gallimberti et al., 1992; Gessa etal., 1992). GHB has been used to decrease the symptoms of opiatewithdrawal, including both heroin and methadone withdrawal (Gallimbertiet al., 1994; Gallimberti et al., 1993). It has analgesic effects thatmake it suitable as a pain reliever (U.S. Pat. No. 4,393,236).Intravenous administration of GHB has been reported to reduceintracranial pressure in patients (Strong, A. 1984). Also,administration of GHB was reported to increase growth hormone levels inpatients (Gessa et al, 1994).

A good safety profile for GHB consumption, when used long term fortreatment of narcolepsy has been reported. Patients have been safelytreated for many years with GHB without development of tolerance(Scharf, 1985). Clinical laboratory tests carried out periodically onmany patients have not indicated organ or other toxicities (Lammers,1993; Scrima, 1990; Scharf, 1985; Mamelack, 1977; Mamelak, 1979; Gessa,1992). The side effects of GHB treatment have been minimal in incidenceand degree of severity, though they include sleepwalking, enuresis,headache, nausea and dizziness (Broughton and Mamelak, 1979; Mamelak etal., 1981; Mamelak et al., 1977; Scrima et al., 1989; Scrima et al.,1990; Scharf et al., 1985). Therefore, it is critical to identify GHBformulations that are resistant to alcohol to avoid accidental GHB dosedumping and the potential side effects that may come along with that andto maintain the positive safety profile for GHB.

GHB and Alcohol

GHB is a central nervous system (CNS) depressant. Alcohol and sedativehypnotics are contraindicated in patients who are using GHB. Theconcurrent use of GHB with other CNS depressants, including but notlimited to opioid analgesics, benzodiazepines, sedating antidepressantsor antipsychotics, general anesthetics, muscle relaxants, and/or illicitCNS depressants, may increase the risk of respiratory depression,hypotension, profound sedation, syncope, and death. If use of these CNSdepressants in combination with GHB is required, dose reduction ordiscontinuation of one or more CNS depressants (including GHB) should beconsidered. In addition, if short-term use of an opioid (e.g. post- orperioperative) is required, interruption of treatment with GHB should beconsidered. See the package insert for Xyrem™.

GHB may impair respiratory drive, especially with overdoses associatedwith interactions with other drugs and alcohol. Prior to taking Xyrem,patients are educated on the risks of concomitant use of alcohol and awarning is also included on the label. GHB formulations such as Xyremare most often taken just before sleep and if a patient hasintentionally or unexpectedly ingested a large amount of alcohol, suchas can occur on a ‘binge night’ of drinking, they ideally will skiptheir dose of GHB that night. However, alcohol is known to impairjudgement and there may be instances where a patient is intoxicated tothe point that they choose to take their GHB dose after drinking ratherthan skip it for that evening. It is therefore important to identifyformulations that are resistant to alcohol induced dose dumping and/orthat inhibit GHB release in increasing concentrations of alcohol.Understanding that moderate and even daily alcohol consumption may occurin patients taking GHB formulations, it is important to still allowmodified release of GHB if the amount of alcohol co-ingested is minimalbut then to rapidly inhibit release if the amount of alcohol increases.

In order to evaluate the alcohol resistance of pharmaceuticalcompositions, the United States Food and Drug Administration (FDA)suggests performing in vitro dissolution tests to compare the kineticsobtained in 0.1 N HCl medium (representative of gastric pH) with thekinetics obtained in the same medium substituted with 5%, 20% and 40%(v/v) ethanol. According to Walden et al. (The Effect of Ethanol on theRelease of Opioids 30 from Oral Sustained-Release Preparations, DrugDevelopment and Industrial Pharmacy, 33:10, 1101-1111, 2007; which isincorporated herein by reference in its entirety), the fact of exposingin vitro a pharmaceutical form over a period of 2 hours is regarded asrepresentative of the exposure time of these pharmaceutical forms invivo.

In addition, healthcare providers should caution patients aboutoperating hazardous machinery, including automobiles or airplanes, untilthey are reasonably certain that GHB does not affect them adversely(e.g., impair judgment, thinking, or motor skills). Patients should notengage in hazardous occupations or activities requiring complete mentalalertness or motor coordination, such as operating machinery or a motorvehicle or flying an airplane, for at least 6, 7, 8 or 9 hours aftertaking the last dose of GHB. Patients should be queried about potentialadverse events, such as excessive daytime sleepiness, CNS depressionrelated events, etc. upon initiation of GHB therapy and periodicallythereafter. These queries should include info regarding additionalcomplications, alcohol for example. See the Xyrem package insert whichis incorporated by reference for all purposes.

In one embodiment described herein, patients are warned that combinationof GHB with alcohol can exacerbate all the effects and adverse eventsassociated with GHB. These effects include the intended effects ofdrowsiness, sedation, and sleep and typically unintended events such asdepressed respiration, CNS depression, excessive drowsiness, hepaticimpairment, and depression, among other things.

Another embodiment of the present invention is a method for treating apatient who is suffering from a disease or condition, or a symptomthereof, treatable with GHB, comprising: administering a salt of GHB ora salt thereof to a patient or determining whether the patient iscurrently on a GHB drug regimen; determining if the patient may alsoingest alcohol; and advising a patient to cease ingestion of alcohol. Insome embodiments, patients benefit from this directive when the patienthas/will have renal impairment.

An essential objective of the present invention is thus to provide analcohol rugged oral pharmaceutical form of at least one activeingredient, preferably GHB, making it possible to avoid or limitincreased release of the active ingredient induced by the consumption ofalcohol, either intentionally or accidentally, during the administrationof this pharmaceutical form. It is also an object of the invention thatthe drug has a modified release profile. Preferably the modified releaseprofile of the drug allows for once nightly, or once daily,administration of the drug.

Alcohol Resistant Dosage Forms

Formulations and dosage forms for the modified release of a drug in thepresence or absence of alcohol are described herein. Formulationsdescribed herein are suited to the sustained, extended, delayed orcontrolled release of drugs, often at high doses, that arecontraindicated with alcohol. In some embodiments, the formulations anddosage forms of the present invention can also include an immediaterelease component. The immediate release component can form part of amodified release unit dosage form or may be a separate immediate releasecomposition. Multi-component dosage forms can comprise a mixture ofmodified release and immediate release components or a mixture ofdifferent modified release components with different release profiles.This mix-and-match system can be used to target unique PK profiles fordifferent drugs as needed.

Immediate and modified release formulations for use in the invention,including materials and methods are shown for example in U.S. patentapplication number 2012/0076865, and U.S. Pat. Nos. 8,771,735, and9,795,567, which are incorporated by reference in their entiretiesherein.

Modified release profiles are also described in (USP XXV, CDER, FDA,Rockville, Md.), extended release profiles are referenced by FDAGuidelines (“Extended Release Oral Dosage Forms: Development,Evaluation, and Application of In Vitro/In Vivo Correlations”, Food andDrug Administration, CDER, September 1997, Page 17), and immediaterelease profile are referenced by FDA guidelines (“Dissolution Testingof Immediate Release Solid Oral Dosage Forms”, issued August 1997,Section IV-A), all of which are incorporated herein by reference intheir entireties as well as the following patents, patent applicationsand other cited references.

Modified release dosage forms permit the release of the activeingredient over an extended period of time in an effort to maintaintherapeutically effective plasma levels over similarly extended timeintervals, improve dosing compliance, and/or to modify otherpharmacokinetic properties of the active ingredient, such as delay onsetof release or change conditions under which release occurs. Modifiedrelease formulations of the invention may provide a sustained releaseprofile of the therapeutic agent in the absence of alcohol. Preferably,a sustained release profile provides not more than about 10% to about50% release of the therapeutic agent within about 1 hour of being in anaqueous buffer, between about 20% to about 70% release within about 2hours to about 4 hours of being in an aqueous buffer, and between about50% to about greater than about 80% release within about 4 hours toabout 10 hours of being in an aqueous buffer.

Modified release formulations of the invention may provide a delayedrelease profile of the therapeutic agent in the absence of alcohol.Preferably, release of the therapeutic agent is delayed during gastrictransit following ingestion. In specific embodiments, release of thetherapeutic agent is delayed during gastric transit following ingestionand having not more than about 0% to 40% release of the therapeuticagent within about 1 hour to about 2 hours of being in an acidic aqueousbuffer (pH<5). In other embodiments, release of the therapeutic agent isdelayed during exposure to the acidic aqueous buffer (pH<5), and thenrelease of the therapeutic agent increases after the formulation issubsequently exposed to a non-acidic (pH>5) aqueous solution such thatrelease of the therapeutic agent increases to between about 50% to about100% release within about 1 hour of being in said non-acidic aqueoussolution; or to between about 10% to about 70% release within about 1hour to about 4 hours of being in said non-acidic aqueous solution. Inthe dissolution testing guideline for modified release profiles, such asthose used in the present invention, material dissolves over a period oftime, and its dissolution is measured at given intervals during thisperiod. A minimum of three time points is recommended and generallycover early, middle and late stages of the dissolution profile (seeGuidance for Industry, SUPAC-MR: Modified Release Solid Oral DosageForms,” Food and Drug Administration, CDER, September 1997). Thepreferred dissolution apparatus is USP apparatus I (basket) or II(paddle), used at recognized rotation speeds, e.g., 100 rpm for thebasket and 50-75 rpm for the paddle.

Other modified or controlled release dissolution profiles as desirablefor use in the invention are described in US 20120076865 incorporatedherein.

Immediate release dosage forms are considered those that have not beenengineered to modify or control the release of the active ingredient.Immediate release profiles typically provide between about 70% and about100% release of the therapeutic agent after about 5 minutes to about 60minutes of being in an aqueous buffer. Immediate release preferablyprovides dissolution profiles wherein greater than 90% of the drugincluded in the immediate release component is released from theimmediate release component within the first hour after administration.In the dissolution testing guidelines, materials which dissolve at least80% in the first 30 to 60 minutes in solution qualify as immediaterelease profiles. (“Dissolution Testing of Immediate Release Solid OralDosage Forms”, issued August 1997, Section IV-A). Therefore, immediaterelease solid oral dosage forms permit the release of most, or all, ofthe active ingredient over a short period of time, such as 60 minutes orless, and make rapid absorption of the drug possible.

A multiphase release profile (i.e., a composition containing animmediate release component and at least one modified release component)may also be employed to attain one or more combinations of release ratesto attain more specific therapeutic objectives such as a portion of drugreleasing immediately, followed by an extended release of the remainder.In some embodiments, the formulations for use in the invention comprisea drug carrier core selected from irregular granules, regular granules,spheronized granules, nanoparticles, drug-loaded non-pareils,micro-particles, pellets, beads, mini-tablets, tablets and/or capsules(hard and/or soft gelatin). In some embodiments, the drug carrier corefor use in the invention comprises drug crystals. Suitable cores aredescribed in Aulton's ‘Pharmaceutics—The Design and Manufacture ofMedicines’, Chapter 32 (Aulton and Taylor; Aulton's Pharmaceutics 4^(th)Edition, published Jun. 19, 2013) and Qiu Y., et al. ‘Developing SolidOral Dosage Forms’, Chapters 33 and 34 (Qiu Y., et al., Developing SolidOral Dosage Forms 1^(st) Edition; published Dec. 19, 2008), each ofwhich is hereby incorporated by reference in its entity for allpurposes.

In some embodiments, the drug carrier core can be the size and/or shapeof a pellet, bead, mini-tablet or tablet.

In particular embodiments, the formulations for use in the inventioncomprise at least two drug carrier cores each comprising a core selectedfrom granules, nanoparticles, micro-particles, pellets, mini-tablets,tablets and/or capsules (hard and/or soft gelatin). In certainembodiments, the formulations for use in the invention comprise at leasttwo drug carrier cores wherein at least one core comprises drugcrystals.

In certain embodiments, the formulations for use in the invention areprovided as a unit dosage form selected from tablets, mini-tablets,capsules, caplets, beads, pellets, granules, sachets, crystals orpowders. In some embodiments, the unit dosage form may be a liquid orsuspension. It is generally understood that “tablets” are meant to bethose of tablet dosage forms of the art which generally are in the rangeof 50 mg up to 2.0 gram. Tablets can include matrix tablets, osmotictablets, bi-layer tablets, orally disintegrating tablets, effervescenttablets and lozenges. Minitablets or mini-tablets are known in the artto be around 5 to 50 mg and typically 1 to 5 mm or preferably 1.5 to 3mm. It is understood that drug carrier cores of the invention maycomprise particles which are less than 5 mg. It is also understood thatin certain embodiments, drug carrier cores of the invention compriseparticles that are from 10 to 5000 microns in diameter. Pellets aremultiparticulate forms that typically range from 300 to 3000 microns,from 600 to 3000 microns or preferably from 800 to 1500 microns.Granules are smaller and typically made up of small, fine particles.

Solid dosage forms or drug carrier cores for use in the invention may bemade by a number of techniques known in the art including, but notlimited to, compression and granulation. In addition, smaller forms,such as for example, pellets (either coated or uncoated) can becompressed into a larger form, such as for example a tablet or pill ofany size or shape using methods such as, for example, those described inU.S. Pat. No. 4,684,516 and Bodmeier, R. (1997) European Journal ofPharmaceutics and Biopharmaceutics, 43(1), 1-8) which are incorporatedherein by reference. Processes often used for making dosage forms of theinvention also include wet granulation, dry granulation, extrusion andspheronization, hot melt extrusion, milling, sieving and blending.

An outer or external functional coating is typically applied to oraldosage forms in order to mask taste, odor or color; provide physical orchemical protection for the active ingredient/drug; control the releaseof the active ingredient from the formulation; protect the activeingredient from the harsh environment of the stomach (i.e. entericcoating); or protect the subject from unwanted gastrointestinal sideeffects. Prior to applying an external coating, a seal-coating (alsoreferred to as a sub-coating) may first be applied. Sub-coatings can actto smooth the product surfaces, enhance the adherence of the final,outer coat, prevent migration of the drug from the core to thefunctional coat, and/or to protect the active ingredient from prematuredegradation. The present invention also shows that the outer functionalcoating can act to prevent or decrease alcohol-induced dose dumping. Thetype and/or thickness of the seal coat or the final coating(s) may bevaried in order to alter product characteristics, such as dissolution.The external or functional coatings are targeted to be about 5-60% byweight (of the drug carrier core) and seal coats are targeted to beabout 1-5%, preferably about 2%, by weight. Sub-coats are generallythought of as “non-functional” in that they are not utilized to controltiming or placement of release of the active ingredient; however, it isconsidered that certain sub-coatings may act as such “functional”coatings. For the purpose of the present invention, “functionalcoatings” are intended to include enteric coatings, time-releasecoatings, pH-dependent coatings, ethanol rugged coatings, or other whichcontrol the timing or placement of release of the active ingredient. Insome exemplified embodiments of the invention, the one or more separatecoatings or layers of the functional coating together constitute about40% or less, 30% or less, 20% or less, or 15% or less of the totaldosage form targeted by weight. In preferred embodiments, the firstfunctional coating is about 10-20% of the total dosage form targeted byweight. In other preferred embodiments, a second or outer functionalcoating is about 1-10% of the total dosage form targeted by weight.

Unless stated otherwise, the amount of coatings or layers describedherein (the “coating weight”) is expressed as the percentage weight gainprovided by the coating, relative to the initial weight of the drugcarrier core prior to the application of said coating. Thus, a 10% (w/w)coating weight refers to a coating which increases the weight of a drugcarrier core by 10%. Further, if the drug carrier core already has oneor more coatings, the weight of the next coating is based on the weightof the core and the first coating. Thus, for a drug carrier corecomprising a 20% w/w functional coating disposed over a 5% (w/w)sub-coating which is disposed over a drug carrier core, the 5% (w/w)sub-coating on the drug carrier core would increase the weight of saidcore by 5% and the 20% (w/w) functional coating would increase theweight of the sub-coated drug carrier core by 20%.

Methods for coating any component of a solid dosage form including thecore, matrix and/or final form include, for example, spray coating andpan coating; however, any known method in the art may be used. Suchpolymer coating methods are described in Remington, The Science andPractice of Pharmacy, 22^(nd) Ed. 2013.

Coating materials for use in the invention, including ethylcellulosematerials, may be readily commercially available, such as for example,ETHOCEL ethylcellulose polymers. Where ethylcellulose is used to formthe functional coating, the physical characteristics of the coatingcomposition and residual shell may be modified by adjusting themolecular weight of the ethylcellulose. For example, different grades ofethylcellulose, including, but not limited to, 4 cP, 7 cP, 10 cP, and 20cP grades, may be used to achieve a coating composition having desiredphysical characteristics. Polymethacrylate polymers for use in coatingsof the invention are readily commercially available, and include, forexample, Eudragit RS and RL.

In certain embodiments of the invention, the formulation comprises acoated drug carrier core comprising a core comprising an active agent, afirst coating disposed over the core, and an optional second coatingdisposed over the first coating. In certain embodiments, the firstcoating is present at about 5%-60% w/w, inclusive of all values andsubranges therebetween, including, but not limited to, 5-10%, 5-15%,5-20%, 5-25%, 5-30%, 5-35%, 5-40%, 5-45%, 5-50%, 5-55%, 10-15%, 10-20%,10-25%, 10-30%, 10-35%, 10-40%, 10-45%, 10-50%, 10-55%, 10-55%, 10-60,15-20%, 15-25%, 15-30%, 15-35%, 15-40%, 15-45%, 15-50%, 15-55%, 15-60%,20-25%, 20-30%, 20-35%, 20-40%, 20-45%, 20-50%, 20-55%, 20-60%, 25-30%,25-35%, 25-40%, 25-45%, 25-50%, 25-55%, 25-60%, 30-35%, 30-40%, 30-45%,30-50%, 30-55%, 30-60%, 35-40%, 35-45%, 35-50%, 35-55%, 35-60%, 40-45%,40-50%, 40-55%, 40-60%, 45-50%, 45-55%, 45-60%, 50-55%, 50-60%, 55-60%w/w; 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%,19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%,45%, 50%, 55% and 60%.

In certain embodiments of the invention, the formulation comprises acoated drug carrier core comprising a core comprising an active agent, afirst coating disposed over the core, and a second coating, or “topcoating” disposed over the first coating. In certain embodiments, thefirst coating is present at about 5%-40% w/w, inclusive of all valuesand subranges therebetween, and the second coating is present at about1%-25% w/w, inclusive of all values and subranges therebetween.

In particular embodiments, the first coating is present at about 5-10%,5-15%, 5-20%, 5-25%, 5-30%, 5-35%, 5-40%, to 10-15%, 10-20%, 10-25%,10-30%, 10-35%, 10-40%, 15-20%, 15-25%, 15-30%, 15-35%, 15-40%, 20-25%,20-30%, 20-35%, 20-40%, 25-30%, 25-35%, 25-40%, 30-35%, 30-40%, or35-40% w/w and the second coating is present at about 1%-5%, 1-7%,1-10%, 1-15%, 1-20%, 1-25%, 2%-5%, 2-8%, 2-10%, 3%-5%, 3-8%, 3-10%,3-12%, 4%-6%, 4-8%, 4-10%, 4-12%, 5-15%, 5-20%, 5-25%, 10-15%, 10-20%,10-25%, 15-20%, 15-25%, or 20-25% w/w.

In other embodiments the first coating is present at about 5-10%, 5-12%,5-15%, 5-20%, 5-25%, 7-12%, 7-15%, 7-20%, 7-25%, 10-15%, 10-17%, 10-20%,10-25%, 12-15%, 12-17%, 12-20%, 12-25%, 15-17%, 15-20%, or 15-25%, w/wand the second coating is present at about 1%-5%, 1-7%, 1-10%, 2%-5%,2-8%, 2-10%, 3%-5%, 3-8%, 3-10%, 4%-6%, 4-8%, 4-10%, 5-10%, 5-12%,5-15%, 7-10%, 7-12%, 7-15%, 10-12% or 10-15% w/w.

In certain embodiments the first coating is present at about 5-15%,5-20%, 7-15%, 7-17%, 7-20%, 10-15%, 10-17%, 10-20%, 12-15%, 12-17%,12-20%, 15-17%, or 15-20% w/w, and the second coating is present atabout 1-5%, 1-7%, 1-10%, 2-5%, 2-8%, 2-10%, 3-5%, 3-8%, 3-10%, 4-6%,4-8%, 4-10%, or 5-10% w/w.

In particular embodiments the first coating is present at about 5-20%,7-17%, 7-20%, 10-17%, 10-20%, 12-15%, 12-17%, 12-20%, 15-17%, or 15-20%w/w, and the second coating is present at about 1-5%, 1-7%, 2-5%, 2-8%,3-5%, 3-8%, 4-6%, or 4-8% w/w. In certain embodiments, the first coatingis present at about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%,16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% w/w, and the secondcoating is present at about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%,11%, 12%, 13%, 14% or 15% w/w.

In certain embodiments, the first coating is present at about 5-30% w/wand the second coating is present at about 1-15% w/w. In particularembodiments, the first coating is present at about 5-25% w/w and thesecond coating is present at about 1-10% w/w. In other embodiments, thefirst coating is present at about 10-30% w/w and the second coating ispresent at about 3-15% w/w. In yet other embodiments, the first coatingis present at about 10-25% w/w and the second coating is present atabout 3-10% w/w. In still other embodiments, the first coating ispresent at about 10-20% w/w and the second coating is present at about3-8% w/w.

In other embodiments, the first coating is present at about 10% w/w andthe second coating is present at about 3% w/w. In yet other embodiments,the first coating is present at about 12% w/w and the second coating ispresent at about 3% w/w. In still other embodiments, the first coatingis present at about 15% w/w and the second coating is present at about3% w/w. In certain embodiments, the first coating is present at about17% w/w and the second coating is present at about 3% w/w. In particularembodiments, the first coating is present at about 20% w/w and thesecond coating is present at about 3% w/w. In other embodiments, thefirst coating is present at about 25% w/w and the second coating ispresent at about 3% w/w. In yet other embodiments, the first coating ispresent at about 10% w/w and the second coating is present at about 5%w/w. In still other embodiments, the first coating is present at about12% w/w and the second coating is present at about 5% w/w. In certainembodiments, the first coating is present at about 15% w/w and thesecond coating is present at about 5% w/w. In particular embodiments,the first coating is present at about 17% w/w and the second coating ispresent at about 5% w/w. In other embodiments, the first coating ispresent at about 20% w/w and the second coating is present at about 5%w/w. In yet other embodiments, the first coating is present at about 25%w/w and the second coating is present at about 5% w/w. In still otherembodiments, the first coating is present at about 10% w/w and thesecond coating is present at about 8% w/w. In particular embodiments,the first coating is present at about 12% w/w and the second coating ispresent at about 8% w/w. In certain embodiments, the first coating ispresent at about 15% w/w and the second coating is present at about 8%w/w. In other embodiments, the first coating is present at about 17% w/wand the second coating is present at about 8% w/w. In yet otherembodiments, the first coating is present at about 20% w/w and thesecond coating is present at about 8% w/w. In still other embodiments,the first coating is present at about 25% w/w and the second coating ispresent at about 8% w/w. In particular embodiments, the first coating ispresent at about 10% w/w and the second coating is present at about 10%w/w. In certain embodiments, the first coating is present at about 12%w/w and the second coating is present at about 10% w/w. In otherembodiments, the first coating is present at about 15% w/w and thesecond coating is present at about 10% w/w. In yet other embodiments,the first coating is present at about 17% w/w and the second coating ispresent at about 10% w/w. In still other embodiments, the first coatingis present at about 20% w/w and the second coating is present at about10% w/w. In certain embodiments, the first coating is present at about25% w/w and the second coating is present at about 10% w/w.

In certain embodiments, the first coating comprises a blend of celluloseand polymethacrylate polymers at a ratio of about 1:3 to 3:1 and ispresent at about 5-30% w/w and the second coating comprises a blend ofcellulose and polymethacrylate polymers at a ratio of about 1:3 to 3:1and guar gum (guar gum added at 1-10% w/w of the cellulose polymer) andthe second coating is present at about 1-15% w/w. In particularembodiments, this first coating is present at about 5-25% w/w and thissecond coating is present at about 1-10% w/w. In other embodiments, thisfirst coating is present at about 10-30% w/w and this second coating ispresent at about 3-15% w/w. In yet other embodiments, this first coatingis present at about 10-25% w/w and this second coating is present atabout 3-10% w/w. In still other embodiments, this first coating ispresent at about 10-20% w/w and this second coating is present at about3-8% w/w. In further embodiments, the cellulose polymer isethylcellulose and the polymethacrylate polymer is methacrylicacid-ethyl acrylate co-polymer 1:1. In further embodiments theethylcellulose and the methacrylic acid-ethyl acrylate co-polymer arepresent at a weight ratio of 3:1 to 1:3. In further embodiments, theethylcellulose and the methacrylic acid-ethyl acrylate co-polymer arepresent at a weight ratio of 1:2. In other further embodiments, theethylcellulose and the methacrylic acid-ethyl acrylate co-polymer arepresent at a weight ratio of 1:1. In still other further embodiments,the ethylcellulose and the methacrylic acid-ethyl acrylate co-polymerare present at a weight ratio of 2:1. In particular embodiments, boththe first and second coating comprise a blend of ethylcellulose and themethacrylic acid-ethyl acrylate co-polymer at a weight ratio of 1:1, andthe second coating comprises guar gum at 2-8% w/w of ethylcellulose. Inother embodiments, the first coating comprises a blend of ethylcelluloseand the methacrylic acid-ethyl acrylate co-polymer at a weight ratio of1:2, and the second coating comprise a blend of ethylcellulose and themethacrylic acid-ethyl acrylate co-polymer at a weight ratio of 1:1 andguar gum at 2-8% w/w of ethylcellulose. In other embodiments, the firstcoating comprises a blend of ethylcellulose and the methacrylicacid-ethyl acrylate co-polymer at a weight ratio of 1:1, and the secondcoating comprise a blend of ethylcellulose and the methacrylicacid-ethyl acrylate co-polymer at a weight ratio of 1:2 and guar gum at2-8% w/w of ethylcellulose. In other embodiments, the first coatingcomprises a blend of ethylcellulose and the methacrylic acid-ethylacrylate co-polymer at a weight ratio of 2:1, and the second coatingcomprise a blend of ethylcellulose and the methacrylic acid-ethylacrylate co-polymer at a weight ratio of 1:1 and guar gum at 2-8% w/w ofethylcellulose. In other embodiments, the first coating comprises ablend of ethylcellulose and the methacrylic acid-ethyl acrylateco-polymer at a weight ratio of 1:1, and the second coating comprise ablend of ethylcellulose and the methacrylic acid-ethyl acrylateco-polymer at a weight ratio of 2:1 and guar gum at 2-8% w/w ofethylcellulose.

In other embodiments, the first coating comprises a blend of celluloseand polymethacrylate polymers at a ratio of about 1:3 to 3:1 and ispresent at about 10-25% w/w and the second coating comprises a blend ofcellulose and polymethacrylate polymers at a ratio of about 1:3 to 3:1and guar gum at 1-10% w/w of the cellulose polymer and is present atabout 3-10% w/w. In other embodiments, this first coating is present atabout 10% w/w and this second coating is present at about 3% w/w. In yetother embodiments, this first coating is present at about 12% w/w andthis second coating is present at about 3% w/w. In still otherembodiments, this first coating is present at about 15% w/w and thissecond coating is present at about 3% w/w. In certain embodiments, thisfirst coating is present at about 17% w/w and this second coating ispresent at about 3% w/w. In particular embodiments, this first coatingis present at about 20% w/w and this second coating is present at about3% w/w. In other embodiments, this first coating is present at about 25%w/w and this second coating is present at about 3% w/w. In yet otherembodiments, this first coating is present at about 10% w/w and thissecond coating is present at about 5% w/w. In still other embodiments,this first coating is present at about 12% w/w and this second coatingis present at about 5% w/w. In certain embodiments, this first coatingis present at about 15% w/w and this second coating is present at about5% w/w. In particular embodiments, this first coating is present atabout 17% w/w and this second coating is present at about 5% w/w. Inother embodiments, this first coating is present at about 20% w/w andthis second coating is present at about 5% w/w. In yet otherembodiments, this first coating is present at about 25% w/w and thissecond coating is present at about 5% w/w. In still other embodiments,this first coating is present at about 10% w/w and this second coatingis present at about 8% w/w. In particular embodiments, this firstcoating is present at about 12% w/w and this second coating is presentat about 8% w/w. In certain embodiments, this first coating is presentat about 15% w/w and this second coating is present at about 8% w/w. Inother embodiments, this first coating is present at about 17% w/w andthis second coating is present at about 8% w/w. In yet otherembodiments, this first coating is present at about 20% w/w and thissecond coating is present at about 8% w/w. In still other embodiments,this first coating is present at about 25% w/w and this second coatingis present at about 8% w/w. In particular embodiments, this firstcoating is present at about 10% w/w and this second coating is presentat about 10% w/w. In certain embodiments, this first coating is presentat about 12% w/w and this second coating is present at about 10% w/w. Inother embodiments, this first coating is present at about 15% w/w andthis second coating is present at about 10% w/w. In yet otherembodiments, this first coating is present at about 17% w/w and thissecond coating is present at about 10% w/w. In still other embodiments,this first coating is present at about 20% w/w and this second coatingis present at about 10% w/w. In certain embodiments, this first coatingis present at about 25% w/w and this second coating is present at about10% w/w. In further embodiments, the cellulose polymer is ethylcelluloseand the polymethacrylate polymer is methacrylic acid-ethyl acrylateco-polymer 1:1. In yet further embodiments the ethylcellulose and themethacrylic acid-ethyl acrylate co-polymer are present at a weight ratioof 3:1 to 1:3. In further embodiments, the ethylcellulose and themethacrylic acid-ethyl acrylate co-polymer are present at a weight ratioof 1:2. In other further embodiments, the ethylcellulose and themethacrylic acid-ethyl acrylate co-polymer are present at a weight ratioof 1:1. In still other further embodiments, the ethylcellulose and themethacrylic acid-ethyl acrylate co-polymer are present at a weight ratioof 2:1. In particular embodiments, both the first and second coatingcomprise a blend of ethylcellulose and the methacrylic acid-ethylacrylate co-polymer at a weight ratio of 1:1, and the second coatingcomprises guar gum at 2-8% w/w of ethylcellulose. In other embodiments,the first coating comprises a blend of ethylcellulose and themethacrylic acid-ethyl acrylate co-polymer at a weight ratio of 1:2, andthe second coating comprise a blend of ethylcellulose and themethacrylic acid-ethyl acrylate co-polymer at a weight ratio of 1:1 andguar gum at 2-8% w/w of ethylcellulose. In other embodiments, the firstcoating comprises a blend of ethylcellulose and the methacrylicacid-ethyl acrylate co-polymer at a weight ratio of 1:1, and the secondcoating comprise a blend of ethylcellulose and the methacrylicacid-ethyl acrylate co-polymer at a weight ratio of 1:2 and guar gum at2-8% w/w of ethylcellulose. In other embodiments, the first coatingcomprises a blend of ethylcellulose and the methacrylic acid-ethylacrylate co-polymer at a weight ratio of 2:1, and the second coatingcomprise a blend of ethylcellulose and the methacrylic acid-ethylacrylate co-polymer at a weight ratio of 1:1 and guar gum at 2-8% w/w ofethylcellulose. In other embodiments, the first coating comprises ablend of ethylcellulose and the methacrylic acid-ethyl acrylateco-polymer at a weight ratio of 1:1, and the second coating comprise ablend of ethylcellulose and the methacrylic acid-ethyl acrylateco-polymer at a weight ratio of 2:1 and guar gum at 2-8% w/w ofethylcellulose.

In certain embodiments, the first coating comprises a blend of two ormore polymers. In some embodiments, the polymer blend comprises at leasttwo polymers which are ethanol-soluble. In further embodiments, thefirst coating comprises a blend of least one polymer with pH-dependentdissolution and at least one polymer with pH-independent dissolutionproperties.

In some embodiments, the polymer blend comprises at least two polymerswith pH-independent dissolution properties or at least two polymers withpH-dependent dissolution properties.

In some embodiments, the polymer with pH-independent dissolutionproperties is selected from ethyl cellulose and/or ethyl acrylate-methylmethacrylate co-polymer and/or ethyl acrylate-methylmethacrylate-trimethylammonioethyl methacrylate chloride co-polymer. Inspecific embodiments, the ethyl acrylate-methylmethacrylate-trimethylammonioethyl methacrylate chloride co-polymer ispresent at a ratio from about 1:2:0.1 to 1:2:0.2.

In some embodiments, the polymer with pH-dependent dissolutionproperties is selected from methacrylic acid ethyl acrylate co-polymerand/or butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methylmethacrylate co-polymer and/or methacrylic acid methyl methacrylateco-polymer and/or methyl acrylate-methyl methacrylate-methacrylic acidco-polymer. In specific embodiments, the methacrylic acid-ethyl acrylateco-polymer is methacrylic acid-ethyl acrylate co-polymer 1:1.

In particular embodiments, the first coating comprises a blend ofcellulose and polymethacrylate polymers. In further embodiments, thecellulose and polymethacrylate polymers are present at a ratio of about50:1 to 1:50, 25:1 to 1:25, 10:1 to 1:10, 5:1 to 1:5 3:1 to 1:3 or 2:1to 1:2. In still further embodiments, the cellulose and polymethacrylatepolymers are present at a weight ratio of about 3:1 to 2:3. In yetfurther embodiments, the cellulose and polymethacrylate polymers arepresent at a weight ratio of about 1:1.

In particular embodiments, the second coating comprises a single polymer(such as ethylcellulose) or a blend of at least two polymers (such asethylcellulose and a polymethacrylate). In some embodiments, the secondcoating further comprises a polysaccharide gum such as acacia gum, guargum, tragacanth gum or xanthan gum. In certain embodiments, the secondcoating is present at about 1%-50% w/w, inclusive of all values andsubranges therebetween, e.g., about 1%-5%, 1-10%, 1-15%, 1-20%, 1-25%,1-30%, 1-35%, 1-40%, 1-45%, 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 5-35%,5-40%, 5-45%, 5-50%, 10-15%, 10-20%, 10-25%, 10-30%, 10-35%, 10-40%,10-45%, 10-50%, 15-20%, 15-25%, 15-30%, 15-35%, 15-40%, 15-45%, 15-50%,20-25%, 20-30%, 20-35%, 20-40%, 20-45%, 20-50%, 25-30%, 25-35%, 25-40%,25-45%, 25-50%, 30-35%, 30-40%, 30-45%, 30-50%, 35-40%, 35-45%, 35-50%,40-45%, 40-50%, 45-50%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%,12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%,26%, 27%, 28%, 29%, 30%, 35%, 40%, 45% and 50%.

In some embodiments, the drug carrier core further comprises a sub-coator seal-coat which is applied prior to applying the first coatingmaterial as described above. In certain embodiments, the sub-coat orseal-coat comprises hydroxypropyl cellulose polymer. In specificembodiments, the sub-coat or seal-coat is applied, from an aqueoussolution, to the drug carrier core to a target level of about 2-15% w/w,inclusive of all values and subranges therebetween, e.g., about 2-3%,3-4%, 4-5%, 5-6%, 5-8%, 5-10%, 5-12%, 6-8%, 6-10%, 6-12%, 6-15%, 8-10%,8-12%, 8-15%, 10-12%, and 10-15% w/w.

Additional excipients for use in dosage forms or drug carrier cores ofthe invention include, but are not limited to, binders, lubricants,glidants, disintegrants, diluents, coloring agents, suspension agents orflavoring agents, and the same excipient may be used for more than onefunction in a given formulation. Such excipients are described inRemington, The Science and Practice of Pharmacy, 22^(nd) Ed. 2013, whichis incorporated herein by reference in its entirety.

Other commonly used pharmaceutically acceptable excipients which may besuitable for use in the present invention include, but are not limitedto, water, magnesium stearate, starch, lactose, microcrystallinecellulose, stearic acid, sucrose, talc, silicon dioxide, gelatin, acaciaand dibasic calcium phosphate (Baldrick, P. (2000) Regul. Toxicol.Pharmacol. October 32(2):210; incorporated herein by reference.)Excipients are combined with active ingredients for example to enhanceappearance, improve stability, aid processing or aid disintegrationafter administration, but many other excipient functions are known inthe art that can be applied to oral dosage forms of the presentinvention. Classes of excipients which are often used and suitable foruse in the present invention include but are not limited to, natural,modified-natural or synthetic mono-, oligo- or polysaccharides whereoligo- and polysaccharides may or may not be physically or chemicallycrosslinked; natural, modified-natural or synthetic mono-, oligo- andpolypeptides or proteins where oligo- and polypeptides and proteins mayor may not be physically or chemically crosslinked; synthetic oligomersand polymers that may or may not be physically or chemicallycrosslinked; monomeric, hydrophobic, hydrophilic or amphoteric organicmolecules; inorganic salts or metals; and combinations thereof.Accordingly, therapeutic agents used herein such as, for example, GHB,paracetamol, codeine or oxycodone may be combined with any excipient(s)known in the art that allows tailoring its performance duringmanufacturing, administration and/or its in vitro and in vivoperformance.

Material which helps to hold the bulk of a product together and/or helpsto maintain the product in a desired shape is known as a “binder” or“granulator”. Binders suitable for use in the present invention areexemplified by, but are not limited to, sugars, gelatin, gums,microcrystalline cellulose and other modified celluloses, waxes orsynthetic polymers like polyethylene glycol or polyvinyl pyrrolidone.Additional excipients often utilized in product formulations arelubricants. These are substances which aid in the manufacturing processas they help minimize clumping of the products and also help releasethem from the manufacturing machinery. A common “lubricant” used forpharmaceutical formulations is magnesium stearate; however, othercommonly used product lubricants include talc, calcium stearate, stearicacid (stearin), hydrogenated vegetable oils, sodium benzoate, leucine,carbowax 4000 and sodium stearyl fumarate all of which may be suitablefor use in the present invention. Glidants also referred to as“flow-aids”, help to keep the powder or dry material of the productsflowing as the products are being made, stopping them from forminglumps. Examples of commonly used glidants which may be suitable for usein the invention include colloidal silicon dioxide, talc, calciumsilicate and magnesium silicate. Disintegrants are often added topharmaceutical formulations to induce breakup of the product or dosageform (i.e. pellet or tablet) when it comes in contact with aqueous fluidin order to help release the drug. The objectives behind addition ofdisintegrants are to increase surface area of the product fragments andto overcome cohesive forces that keep these particles together in aformulation. They do this by promoting wetting and swelling of thedosage form so that it breaks up in the gastrointestinal tract. Somebinders such as starch and cellulose also act as disintegrants. Otherdisintegrants are clays, cellulose derivatives, algins, gums andcrosslinked polymers. Another group of disintegrants called“super-disintegrants” may be utilized. These materials are effective atlow (2-5%) concentrations. “Super-disintegrants” which may be suitablefor use in the present invention include, but are not limited to, sodiumstarch glycolate (SSG), croscarmellose sodium or crosprovidone.

It could be envisaged that a material or materials which help suspend acomposition of the invention in a liquid, for example water, foradministration could be used. Suspension agents (or viscosity modifyingagents) suitable for use in the present invention are exemplified by,but are not limited to, acacia, agar, alginic acid, bentonite, calciumstearate, carbomers, carboxymethylcellulose calcium,carboxymethylcellulose sodium, carrageenan, cellulose (powdered),ceratonia, colloidal silicon dioxide, dextrin, gelatin, guar gum,hectorite, hydrophobic colloidal silica, hydroxyethyl cellulose,hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose,kaolin, magnesium aluminium silicate, maltitol solution, medium-chaintriglycerides, methylcellulose, microcrystalline cellulose,phospholipids, polycarbophil, polyethylene glycol, polyoxyethylenesorbitan fatty acid esters, potassium alginate, povidone, propyleneglycol alginate, saponite, sesame oil, sodium alginate, sodium starchglycolate, sorbitan esters, sucrose, tragacanth, vitamin E polyethyleneglycol succinate or xanthan gum.

pH adjusting agents may be used in the invention and can include acids,bases and many of the compounds/salts found in U.S. Pat. No. 8,263,650.In some embodiments the pH adjusting agent is an acid selected from thegroup of: acetic, acetylsalicylic, barbital, barbituric, benzoic, benzylpenicillin, boric, caffeine, carbonic, citric, dichloroacetic,ethylenediaminetetra-acetic acid (EDTA), formic, glycerophosphoric,glycine, lactic, malic, mandelic, monochloroacetic, oxalic,phenobarbital, phenol, picric, propionic, saccharin, salicylic, sodiumdihydrogen phosphate, succinic, sulfadiazine, sulfamerazine,sulfapyridine, sulfathiazole, tartaric, trichloroacetic, and the like,or inorganic acids such as hydrochloric, nitric, phosphoric or sulfuric,and the like. Preferably the pH adjusting agent should be apharmaceutically acceptable acid as listed in the “Handbook ofPharmaceutical Salts: Properties, Selection and Use” (P. Stahl; JohnWiley & Sons, Aug. 4, 2008; included herein by reference).

GHB is the preferred therapeutic agent for use in formulations of theinvention. Typical concentrations of solid and liquid GHB formulationsare shown in U.S. Pat. Nos. 8,263,650 and 8,324,275.

EXAMPLES Example 1: Demonstrating Enteric Dissolution Behavior UsingEthylcellulose: Methacrylic Acid-Ethyl Acrylate Copolymer at a Ratio of1:1 (% w/w)

Multi-particulate (pellet) drug carrier cores of calcium oxybate(monohydrate) were made by the process of extrusion-spheronisation. 17 gcalcium oxybate (monohydrate), 1.4 g Avicel PH101, 0.6 g LH-31 and 0.6 gKlucel EF were weighed and added into the mixing bowl in CalevaMulti-lab for pre-blending for 1015 minutes at 100 RPM. The Klucel EFaqueous solution (9.6% or 8.3% w/w) was added slowly to the blend. Thewet mass was well mixed for 15 minutes, during which time the mixer wasstopped three to four times for visual checking and manual mixing. Thewet mass was then moved to extruder and extruded through die plate with1.0 mm or 0.8 mm pore size; the subsequent extrudate was rested at roomtemperature for 10 minutes before transferring into the spheronizer tobe processed for 3-5 minutes at approximately 3000 RPM. The drug carriercores (shaped like pellets) were collected and dried in the oven for 2hours at 60° C. Final drug carrier core composition is given in Table 1below.

TABLE 1 Composition of the calcium oxybate drug carrier (pellet) coreComponent Quantity % Ca Oxybate 85.0 Avicel PH101  7.0 LH-31  3.0 KlucelEF  5.0 Water* q.s *removed during the pellet drying process

A binary polymer film coat consisting of a 1:1 (based on % w/w ofpolymer) mix of ethyl cellulose (EC) and Eudragit® L100-55 was appliedto the drug carrier core described. The EC was used as the aqueouspolymer dispersion, Aquacoat® ECD. The mixed polymer film was applieddirectly to the calcium oxybate pellet core.

FIG. 1 shows the in vitro dissolution profile of calcium oxybate from apellet having a polymer film of 30% w/w of the drug carrier core(“DR02”). Dissolution was tested for 2 hours in acid (0.1N HCl) followedby 1 hour in Tris pH 6.8 buffer. The data demonstrates the effectivenessof the polymer mix in suppressing dissolution in acid with rapid releaseat pH 6.8.

Example 2: Demonstrating Enteric Dissolution Behavior UsingEthylcellulose and an Alternate Preparation of Methacrylic Acid-EthylAcrylate Copolymer at a Polymer Blend Ratio of 1:1 (% w/w)

An alternative method of binary polymer film preparation to thatpresented in Example 1 was examined whereby the L-100-55 powder wasreplaced with the aqueous polymer dispersion, L30D-55 (i.e. mixing twocolloidal polymer dispersions, Aquacoat® ECD+Eudragit® L30D-55). As perExample 1, the calcium oxybate pellet core was coated to a total polymerweight gain of 30% w/w (of the starter core eight). The coated-coreswere tested for 2 hours in acid (0.1N HCl) followed by 1 hour in Tris pH6.8 buffer.

FIG. 2 shows the dissolution rate of pellet-shaped calcium oxybate drugcarrier cores coated using the two different Eudragit® preparations.Comparing the powder form (“DR02”; circles) to the aqueous form (“DR04”;squares), it can be seen that similar dissolution profiles were obtainedusing either Eudragit L100-55 source.

Example 2A: Demonstrating Shut Down of Oxybate Release FollowingExposure to Ethanol Via Gel Layer Formation. Bi-Layer Coating ofEC:L100+EC:L100:GG (Guar Gum)

An additional polymer film layer incorporating the polysaccharide guargum (“GG”) was applied to the formulation of DR02 (described in Examples1 and 2). This outer polymer film top coat consisted of EC: L100-55 at a1:1 ratio and guar gum at a level of 5% w/w of the EC polymer content.The outer polymer film coat was applied to a level of 10% w/w of thepellet having the first polymer coating. The resulting pellets weretested for 2 hours in 0.1N HCl followed by 1 hour in Tris pH 6.8 buffer(USP 2, 37 C, 100 rpm, 300 mL). The dissolution profile of thesebi-layer coated formulation is also shown in FIG. 2 (DR03, triangles)and is compared to that of the single layer coated formulations (DR02(circles) and DR04 (squares)).

It can be seen that the additional polymer film on DR03 slows thedissolution rate in both acid and pH 6.8 buffers. Formulation DR03 wasalso tested for resistance to dissolution in the presence of ethanol asshown on the graph (inverted triangles). The most rigorous in vitroethanol challenge as described in the FDA recommendations on evaluatingformulation susceptibility to alcohol-induced dose dumping was applied,i.e. 2 hours exposure to 0.1N HCl containing 40% v/v ethanol.Surprisingly, as shown in FIG. 2, the rate of oxybate release followingexposure to ethanol dramatically decreased.

In addition, a transparent gel layer was observed to surround thosepellets exposed to ethanol. As shown in FIGS. 3A and 3B, a gel layersurrounds the DR03 polymer coated pellets exposed to ethanol (FIG. 3B)whereas it is not present in those exposed only to 0.1N HCl (FIG. 3A).Such gel layer formation in the presence of ethanol has also beenobserved for GHB pellets having a single polymer coat containingethylcellulose and methacrylic acid-ethyl acrylate co-polymer. Thustogether this shows that upon inclusion of 40% v/v EtOH in the firstacid phase dissolution test it is observed that the rate of oxybaterelease is suppressed following an initial release of approximately 10%oxybate, representing release during the period for the hydrogel to formaround the pellet (as shown in FIG. 3), after which, oxybate release issuppressed.

Example 3: Demonstrating an Ethanol Concentration-Dependent Effect onGel Layer Formation. Bi-Layer Coating of Calcium Oxybate Pellet CoresUsing Binary EC+L30D-55 Polymers. Guar Gum Incorporated in the OuterPolymer Film Coat (as Per Example 2A, DR03)

Pellet formulations were prepared as described above for DR03 with abinary EC:L30D-55 (1:1) polymer film coat, applied to a target 30%polymer weight gain (% w/w of the drug carrier core). An outer polymerfilm was then applied consisting of EC:L30D-55 (1:1) polymer mix plusguar gum (GG was used at a concentration of 5% w/w of the EC polymercontent). This top coat was applied to a target 10% weight gain (% w/wof the drug carrier core pellet having the first polymer coat applied).Table 2 below contains a list of materials and equipment used tomanufacture the formulations as described herein. The composition of thecoating suspensions used for the inner layer and the outer guar gumlayer is given in Table 3 also below:

TABLE 2 List of materials and equipment used for manufacture ofprototypes Material/Equipment Supplier/Manufacturer Ethylcellulose(EC20) Colorcon Limited Aquacoat ECD (component I of II) FMC AquacoatGuar gum FMC (component II of II) Eudragit L30D-55 EvonikPolyvinylpyrrolidone (PVP BASF K30) Dibutyl sebacate (DBS) Sigma AldrichDeionised water Elga water systems 2-Propanol (IPA) VWRMini-coater/Drier 2 with Caleva antistatic attachment

TABLE 3 Composition of the coating solutions for Example 3a Quantitybased Quantity on dry to be Dry polymer weighed quantity CoatingFunction Ingredient (%) (g) (g) EC+L30D- Polymer Aquacoat ECD —  41.6712.501 55 Diluent Water —  41.67 — coating Polymer Eudragit —  41.6712.501 L30D-55 solution Diluent Water —  50.83 — (14% polymer content)Total: 178.34 g Guar gum Polymer EC+L30D-55 — 100 15.422 coating coatingsolution solution Polymer Guar gum 0.0526*  0.3689  0.3689 Diluent Water—  40 — (<0.5% guar gum content**) Total: 140.3689 g *Corresponds toEC/gg = 95/5 **0.5% is the maximum recommended guar gum concentration

The graph in FIG. 4 shows the dissolution data generated for the ethanolresilient polymer film system applied to calcium oxybate drug carriercores (Prototype DR013), wherein the coated drug carrier cores, presentas pellets, were tested for 15 minutes in 0.1N HCl, either with orwithout 10%, 20% or 40% ethanol as indicated, followed by testing inTris pH 6.8 buffer as outlined below. The shorter 15 min exposure to0.1N HCl/ethanol was used to better mimic in vivo conditions forco-ingestion of GHB and alcohol.

Thus the dissolution data in FIG. 4 generated over 15 minutes in 0.1NHCl (circles) represents more bio-relevant EtOH exposure time in stomachunder fasted conditions with subsequent dissolution over 2 hours in TrispH 6.8 buffer, representing passage through the small intestine. Asshown, upon inclusion of 10% v/v EtOH in the 15 minute acid phase of thedissolution test (squares), it is observed that there is no impact tosubsequent dissolution rate in the Tris pH 6.8 buffer. Upon inclusion of20% v/v EtOH in the 15 minute acid phase of the dissolution test(triangles), it is observed that, following an initial ‘burst’ releaseof about 10% oxybate in 5 minutes, the subsequent dissolution rate inthe Tris pH 6.8 buffer is repressed over a 2 hour period. Upon inclusionof 40% v/v EtOH in the 15 minute acid phase of the dissolution test(inverted triangles), it is observed that, following an initial ‘burst’release of approximately 5% oxybate in 5 minutes, the rate of oxybaterelease is suppressed in the Tris pH 6.8 buffer. Importantly, thepellets begin to clump after 10-15 minutes in 0.1N HCl containing 20%v/v and 40% v/v ethanol (but not with 0% or 10% ethanol) and thisclumping reflects the formation of the ‘sticky’ hydrogel layer. Thisaccounts for the initial 10% oxybate burst release before the gel layerformation shuts down oxybate release.

To ascertain the strength of the gel layer formed following exposure to20% and 40% ethanol, dissolution studies were extended for up to atleast 5 hours (300 minutes) in Tris pH 6.8 as shown in FIG. 4. As seen,extending the Tris pH 6.8 buffer dissolution time beyond 2 hoursdemonstrates that the polymer coated drug carrier cores exposed to 20%v/v EtOH show a sharp inflection in the oxybate release rate after 2hours, suggesting that the hydrogel has disintegrated, allowing oxybatedissolution, with 100% released within 4.5 hours. Surprisingly, for thepolymer coated drug carrier cores exposed to 40% v/v EtOH, oxybatedissolution rate is significantly supressed even out to 6 hours, withonly about 30% oxybate released. The dissolution data indicates that therate and extent of hydrogel formation is EtOH concentration dependent.

Rheology studies on binary EC: L30D-55 polymer films applied to placebo(sucrose) pellet-shaped drug carrier cores support the dissolutionfindings. FIG. 5 presents the results of a study measuring the change insurface rheology of the binary polymer film coat following exposure toethanol (40% v/v in 0.1N HCl buffer). The study indicates that anelastic gel, indicative of a hydrogel, is formed upon exposure toethanol. The gel takes approximately 10-20 minutes to form and uponremoval of the ethanol medium and transfer to non-ethanol containingmedium (Tris pH 6.8 buffer), the hydrogel continues to form, increasingin gel strength over a 3 hour period. FIG. 5A shows the variation in theshear storage modulus (elastic response, G′) measured at a probefrequency sweep of 1 Hz over time following exposure of polymer coatedplacebo (sucrose) pellet cores to 40% v/v EtOH in 0.1N HCl buffer. Thecurve shows that G′ gives highest response during the first measurement,as expected as the gel coating is in it's infancy in terms of formation.This is followed by a drop in G′, i.e. softening of the surface, overtime for successive probe sweeps as the gel develop. A constant G′ valueis reached after approximately 20 minutes, indicating complete gelformation. FIG. 5B shows the variation in the shear storage modulus(elastic response, G′) measured at a probe frequency sweep of 1 Hz overtime following transfer of polymer coated placebo (sucrose) pellet coresfrom 0.1N HCl buffer containing 40% v/v EtOH to Tris pH 6.8 buffer (noEtOH). The graph shows that the initial G′ value increases significantlyfollowing transfer from the EtOH containing buffer to the EtOH-free Trisbuffer, from approximately 1,400 Pa at the end of the EtOH exposurephase to 2,500 Pa upon transfer to the Tris buffer. This indicates arapid increase in gel mechanical strength. The gel then softens over thenext 40 minutes to a minimum value of approximately 1200 Pa beforeincreasing linearly over the next 3 hours to a final maximum measuredvalue of approximately 4000 Pa, a significant increase in gel mechanicalstrength over time.

Example 4: The Effect on Release Rate of Altering the Composition of theOuter Polymer Film in Bi-Layer Coated Pellets

The Examples above show that the addition of an outer polymer film coatconsisting of EC/L100-55/GG helps to slow the rate of oxybatedissolution from the drug carrier core (here shaped as a pellet and thusalso referred to as a “pellet core”).

In an attempt to further reduce the effect of the outer polymer film onoxybate dissolution, the permeability of the outer coating was alteredby adding the water soluble excipient, polyvinylpyrrolidone (“PVP”).Dissolution studies were performed as above both in the presence andabsence of ethanol.

FIG. 6 is a graph showing the in vitro dissolution profile for GHBformulations both with and without the additional outer polymer filmcoat consisting of EC/L100-55/GG/polyvinylpyrrolidone (“PVP”) whentested for 2 hours in acid (0.1N HCl), followed by 60-90 minutes in TrispH 6.8 buffer. Also shown is the dissolution of the double-coated GHBformulation (DR05) when exposed to 20% and 40% EtOH/acid buffer for 2hours followed by 1 hour exposure to Tris pH 6.8 buffer without EtOH.Comparison is made to DR03 and DR04, demonstrating the effect of outerfilm coat composition on the in vitro dissolution rate both in theabsence and presence of EtOH. As shown in the graph, the PVP-containingformulation, DR05 (squares), produced pellets (coated drug carriercores) with a similar dissolution rate as the single coated formulation(DR04; containing no top coat or PVP (closed circles)) and did not clumpfollowing exposure to 40% v/v ethanol (inverted triangles)). While DR05prevented rapid oxybate release in HCL (squares), oxybate releaseincreased upon ethanol exposure, but with only 14-18% oxybate releasedover 2 hours in 0.1N HCl/20% v/v ethanol and 55-60% oxybate releasedover 2 hours in 0.1N HCl/40% v/v ethanol.

Together the above results show that going from DR04 to DR03 (where atopcoat of EC/L100-55/GG was added) resulted in a reduced rate of drugrelease and the pellets clumped upon gel formation in the presence ofethanol. Further, when the outer topcoat composition was altered toincrease permeability (through the addition of the water solublepolyvinylpyrrolidone) as with DR05 there was reduced clumping. The outerpolymer film has limited impact on oxybate release rate in Tris pH 6.8and also the pellets do not clump when exposed to 40% v/v ethanol. Rapiddose dumping is prevented in the presence of ethanol, with approximately55-60% oxybate release over 2 hours in 0.1N HCl/40% v/v ethanol.

Example 5: Effect of Buffer Composition on Rate of GHB

Dissolution testing on the DR05 formulation described above was repeatedusing different post-HCL (i.e. non-acidic) buffers. Coated drug carriercores, present as pellets, were tested for 2 hours in 0.1N HCl orEtOH/HCL followed by 1 hour in Tris pH 6.8 buffer (“TRIS”; USP 2, 37 C,100 rpm, 300 mL) or 1 hour in pH 6.8 bicarbonate buffer.

As shown in the graph in FIG. 7, the rate of GHB release after exposureto 20% ethanol was reduced in both the Tris-treated orbicarbonate-treated samples.

Example 6: Use of a Sub-Coat with Drug Carrier Cores Containing a HighlyWater Soluble Drug Substance

In order to analyze the impact of the use of a polymer sub-coat on theresultant dissolution profile of binary polymer film coated drug carriercores, calcium oxybate pellet cores (“pellet cores”) were prepared byextrusion-spheronisation to the same composition described in Table 1. Ahydroxypropyl cellulose (HPC) polymer sub-coating was applied, from anaqueous solution, to the pellet cores to a target level of 8% w/w of thepellet core. A functional binary polymer film coat of ethylcellulose andmethacrylic acid-ethylacrylate co-polymer (polymer ratio of 1:1) wasthen applied to a weight gain of 10% w/w of the sub-coated pellet core.The final functional film coat composition is as described for DR04 inExample 2.

The graph in FIG. 8 shows the two-stage dissolution data as presentedfor 1-2 hours exposure to 0.1N HCl buffer followed by 1 hour in Tris pH6.8 buffer both with (circles) and without the sub-coat (invertedtriangles). Two stage dissolution data is also presented for 15 minexposure to 0.1N HCl buffer containing 20% v/v ethanol followed by 1hour exposure to Tris pH 6.8 buffer both with (squares) and without thesub-coat (diamonds). Comparison is made to FIG. 9 which is a graphshowing a sustained release (close to first order) oxybate dissolutionprofile over a 4 hour period under bi-phasic dissolution test conditionsfollowing application of a binary polymer film of ethylcellulose (EC)and methacrylic acid-ethylacrylate co-polymer 1:1 (as Eudragit® L100-55)prepared as a solution in organic solvent to calcium oxybate pelletcores.

Example 7: Incorporation of Alternative Polymethacrylate Polymers

A binary polymer film of ethylcellulose (EC) and methacrylic acid-methylmethacrylate co-polymer 1:1 (as Eudragit® L100) prepared as an aqueousdispersion was applied to calcium 3-hydroxybutyrate (Ca-3HB) pelletcores. The Ca-3HB pellet core was manufactured as per the methoddescribed for the manufacture of Ca oxybate pellet cores of Example 1.The cores were of the same % w/w composition, with the replacement of Caoxybate with Ca-3HB. The Ca-3HB pellets were screened to the same sizedistribution as the Ca oxybate pellets (i.e. 0.8 mm-1.25 mm).

The binary polymer film was applied directly to Ca3HB pellet cores to alevel equivalent to 15% w/w of the pellet core. As shown in the graph inFIG. 10, the incorporation of the Eudragit® L100 polymer with pH 6dissolution trigger point results in an enteric release profile as shownwith complete suppression of hydroxybutyrate release in acid (60 min).

FIG. 11 shows the hydroxybutyrate dissolution profile followingapplication of a binary polymer film of ethylcellulose (EC) andmethacrylic acid-methyl methyacrylate co-polymer 1:2 (as Eudragit® S100)prepared as an aqueous dispersion and applied to calcium3-hydroxybutyrate (Ca-3HB) pellet cores. As above, the binary polymerfilm was applied directly to Ca3HB pellet cores to a level equivalent to15% w/w of the pellet core. The incorporation of the Eudragit® S100polymer with pH 7 dissolution trigger point results in completesuppression of hydroxybutyrate release in acid (120 minutes), followedby extended suppression of release over 2.5 hours in Tris pH 7.5 buffer,above the pH dissolution trigger of S100 buffer over a 5 hour period.After 5 hours exposure to Tris pH 7.5 buffer only approximately 20%hydroxybutyrate is released from the coated pellet core.

FIG. 12 shows the two stage oxybate dissolution profile following theapplication of a binary polymer film of ethylcellulose (as Ethocel™ 20)and methacrylic acid-methyl methacrylate 1:1 co-polymer (as Eudragit®L100) to a calcium oxybate pellet core (closed circles). The pellet corewas prepared as described in Example 1. The binary polymer film wasprepared as a solution in an isopropyl alcohol/water solvent mix at anEC: L100 polymer ratio of 1:2 (based on % w/w dry polymer). The binarypolymer film was applied to a level equivalent to 12% w/w of the pelletcore. Two-stage dissolution data is also presented for 15 minutepre-exposure to 0.1N HCl buffer containing 20% v/v ethanol and 40% v/vethanol followed by 5 hour exposure to Tris pH 6.8 buffer (triangles andinverted triangles respectively). The application of the binary filmresults in a relatively pH-independent extended release of oxybate over6 hours (closed circles). The film is resilient to dissolution changefollowing 15 min exposure to 20% v/v EtOH in acid, (triangles). Upon 15minute pre-exposure of the formulation to 40% v/v EtOH in acid,(inverted triangles), the oxybate dissolution rate increasessignificantly.

Two-stage oxybate dissolution data is also shown following theapplication of a binary polymer ‘topcoat’ to the Ethocel™ 20-L100 coatedpellet cores, (closed squares). The ‘topcoat’ consists of an aqueousdispersion of ethylcellulose and methacrylic acid-ethylacrylate 1:1co-polymer (as Eudragit® L30D-55). The two polymers were used at a ratioof 1:1 (% w/w dry polymer). Guar gum was incorporated at a level of 10%w/w dry polymer content. The ‘topcoat’ polymer film was applied to alevel equivalent to 5% w/w of the coated pellet core. The application ofthe ‘topcoat’ polymer film alters the oxybate dissolution profilesignificantly, with pH-dependent, enteric, in vitro release profileattained—greater suppression of release in acid and greater than 90%oxybate released following 2 hours exposure to Tris pH 6.8 buffer. Theoxybate release profile is largely unchanged following 15 minpre-exposure to 10%, 20% and 40% v/v EtOH, (diamonds, open circles andopen squares respectively).

Example 8: Application of Ethylcellulose-Methacrylic Acid Ethylacrylate1:1 Co-Polymer Binary Polymer Film to Paracetamol Pellet Cores

Multi-particulate (pellet) drug carrier cores of paracetamol were madeby the process of extrusion-spheronisation. The core composition isprovided in Table 4. Core components are weighed and then added to themixing bowl of a Caleva Multi-lab and pre-blended. Water was added tothe mixed dry components until a wet mass was formed. The wet mass wasmixed for an additional 10 minutes then extruded (die plate diameter of1.0 mm). The extrudate was then spheronised and dried to form theparacetamol pellet core.

TABLE 4 Composition of the paracetamol pellet core Component Quantity (%w/w) Paracetamol 10.0 Lactose 40.0 Microcrystalline cellulose 50.0Water* q.s

A binary polymer film coat consisting ethylcellulose (as the 30% aqueousdispersion, Aquacoat® ECD) and methacrylic acid-ethylacrylate 1:1co-polymer (as Eudragit® L30D-55) was applied to paracetamol pelletcores at varying film thickness. The polymer film was prepared as anaqueous dispersion with polymer ratio of 1:1 (based on % w/w drypolymer).

FIG. 13 presents data generated for two-stage in-vitro dissolutiontesting of the binary film coated paracetamol pellets (0.1N HCl-Tris pH6.8 buffer). At all polymer film thicknesses investigated, paracetamolrelease is significantly suppressed in acid. The lag in paracetamolrelease in the Tris pH 6.8 buffer is extended with increasing polymerfilm thickness. In-vitro dissolution data is also presented following 15minute pre-exposure of the coated paracetamol pellets to 0.1N HClcontaining 40% v/v EtOH. A hydrogel is observed around the paracetamolpellets following exposure to the acid-EtOH mix. Paracetamol dissolutionrate following subsequent transfer of the EtOH exposed coated pellets toTris pH 6.8 buffer is suppressed for between approx. 60-120 minutes,depending on the polymer film thickness.

Example 9: Sustained Release Oxybate Prototypes: In Vitro DissolutionCorrelates with In Vivo Pharmacokinetics

Prototypes were prepared for pharmacokinetic evaluation in humans.Calcium oxybate (monohydrate) multi-particulate (pellet) cores wereprepared by extrusion-spheronisation at a batch scale of approximately1.8 Kg (batch sizes can vary, with typical batch sizes ranging from 0.5Kg to 3.0 Kg). The composition of the pellet core is provided in Table5.

TABLE 5 Composition of the calcium oxybate pellet core prepared forhuman PK studies Component Quantity per Batch (kg) Calcium oxybate(monohydrate) 1.530 Microcrystalline cellulose 0.126 HydroxypropylCellulose 0.090 Hydroxypropyl Cellulose, low- 0.054 substituted Purifiedwater* 0.34

The drug carrier core is manufactured by high shear blending the drugsubstance with microcrystalline cellulose, hydroxypropyl cellulose andlow-substituted hydroxypropyl cellulose. An aqueous solution ofhydroxypropyl cellulose (10% w/w) is added to the dry powder undermixing to produce a plastic wet mass for extrusion. The wet mass isextruded (NICA™ E140, GEA Germany) and the extruded mass spheronized(NICA™ S450, GEA Germany). The wet pellets are dried using a fluid beddrier and then screened to the desired size range.

Two different sustained release dosage forms were produced for human PKevaluation:

-   -   1. Sustained release using ethylcellulose-based polymer film        coating (‘SR2’)    -   2. Sustained release using ethylcellulose+methacrylic        acid-ethylacrylate binary polymer film system (‘SR2’)

The ‘SR1’ prototype is produced by directly applying a polymer filmcomprising ethylcellulose (Ethocel Standard 20 Premium), andpolyvinylpyrrolidone (Kollidon K30) to the calcium oxybate (monohydrate)pellet core. The polymer is prepared as a solution in isopropyl alcoholand water and applied to the core via a bottom-spray fluid bed process.The composition of ‘SR1’ is presented in Table 6.

TABLE 6 Composition of ‘SRI’ Prototype for Human PK studies Composi-tion Component Function (% w/w) Calcium oxybate monohydrate ActiveIngredient 79.45 Microcrystalline cellulose Binder & process aid  6.54Hydroxypropyl cellulose Binder and coating  4.67 polymer Hydroxypropylcellulose, low Binder  2.80 substituted (L-HPC) EthylcelluloseFunctional (sustained  4.85 release) polymer film PolyvinylpyrrolidonePolymer film pore former  1.21 TEC Polymer film plasticizer  0.48

The ‘SR2’ prototype is produced by directly applying a binary polymerfilm comprising ethylcellulose (as 30% aqueous dispersion) andmethacrylic acid-ethyl acrylate (1:1) co-polymer (as 30% aqueousdispersion) to the calcium oxybate (monohydrate) pellet core. Thepolymer is prepared as an aqueous dispersion and applied to the core viaa top-spray fluid bed process. The composition of ‘SR2’ is presented inTable 7.

TABLE 7 Composition of ‘SR2’ Prototype for Human PK studies Composi-tion Component Function (% w/w) Calcium oxybate monohydrate ActiveIngredient 76.58 Microcrystalline cellulose Binder & process aid  6.31Hydroxypropyl cellulose Binder and coating  4.50 polymer Hydroxypropylcellulose, low Binder  2.70 substituted (LH-31, Shin Etsu)Ethylcellulose, 30% aqueous Functional polymer  4.50 dispersion (alsocomprising film (pH sodium lauryl sulphate independent and cetylalcohol) dissolution) Methacrylic acid - ethyl acrylate Functionalpolymer  4.50 copolymer (1:1), Type A, 30% film (pH dependent aqueousdispersion (also dissolution, comprising sodium lauryl triggered at pH ≥sulphate and polysorbate 80) 5.5) TEC Polymer film  0.90 plasticizer

The in vitro dissolution profiles for the ‘SR1’ and ‘SR2’ prototypes arepresented in FIG. 14. The dissolution was performed in 900 mL 0.04M Trisbuffer pH 6.8 at 37° C. using USP type II (rotating paddle) apparatuswith paddle speed of 100 rpm. As the ‘SR2’ functional polymer film iscomprised of a 1:1 mixture of pH-independent ethylcellulose andpH-dependent methacrylic acid-ethyl acrylate co-polymer, its dissolutionwas tested under alternative pH conditions to elicit pH response uponmixing both polymer types. The dissolution profiles are presented inFIG. 15 and demonstrate pH-dependent release properties of thecomposition.

The two SR compositions were administered to healthy human volunteerstwo hours after the start of a high-fat, high-calorie breakfast (doseequivalent to 4.5 g sodium oxybate). The PK data is presented in FIG.16. The ‘SR2’ prototype was administered in combination with an aqueous(IR) oxybate solution at a dose ratio of 1:2.5 solution: ‘SR2’respectively. The ‘SR1’ prototype was administered individually at 4.5 gequivalent sodium oxybate. The data demonstrates that the fasterreleasing prototype in vitro, ‘SR2’, results in higher relative oxybatebioavailability. As shown in the graphs, the ‘SR1’ prototypedemonstrates significantly lower exposure compared to the ‘SR2’prototype.

The effect of 15 minute exposure to 20% v/v ethanol in acid (0.1N HCl)on the resultant dissolution profile of the binary polymer film ‘SR2’prototype in Tris pH 6.8 buffer is presented in FIG. 17. It can be seenthat exposure to ethanol results in a subsequent slowing of oxybatedissolution from the coated pellet. Although not wishing to be bound byany one theory, a comparison to the dissolution of the ‘SR1’ prototypesuggests that the slowdown in oxybate dissolution might result in asignificant decrease in oxybate bioavailability.

Example 10: Pharmacokinetics of Delayed Release Oxybate Examples

Delayed (enteric) release oxybate prototypes were prepared forpharmacokinetic evaluation in humans. Calcium oxybate (monohydrate)pellet cores were prepared as described in Example 9. Two delayedrelease dosage forms were produced for human PK evaluation:

-   -   1. Delayed release using methacrylic acid-ethyl acrylate based        polymer film coating (‘DR1’)    -   2. Delayed release using ethylcellulose+methacrylic        acid-ethylacrylate binary polymer film system (‘DR2’)

The ‘DR1’ prototype is produced by applying a methacrylic acid-ethylacrylate (1:1) co-polymer based film, (as AcrylEze® II, (Colorcon, USA))to a hydroxypropyl cellulose sub-coated calcium oxybate (monohydrate)pellet core. The polymer is prepared as an aqueous suspension andapplied via a bottom-spray fluid bed process. The composition of ‘DR1’is presented in Table 8.

TABLE 8 Composition of ‘DR’Prototype for Human PK studies Composi- tionComponent Function (% w/w) Calcium oxybate monohydrate Active Ingredient60.53 Microcrystalline cellulose Binder & process  4.99 aidHydroxypropyl cellulose Binder and  9.26 coating polymer Hydroxypropylcellulose, low Binder  2.15 substituted (L-HPC) AcrylEze ® IIMethacrylic acid Functional 23.07 and ethyl aciylate (enteric) copolymerpolymer film Talc Titanium dioxide Poloxamer 407 Calcium silicate Sodiumbicarbonate Sodium lauryl sulphate

The ‘DR2’ prototype (for clarification, this is different from “DR02”listed in the above Examples) is produced by directly applying a binarypolymer film comprising ethylcellulose and methacrylic acid-ethylacrylate (1:1) co-polymer to the calcium oxybate (monohydrate) pelletcore. The ethylcellulose and methacrylic acid-ethyl acrylate (1:1)co-polymer are prepared at an ethylcellulose:copolymer ratio of 1:2based on % w/w of dry polymer content. The ethylcellulose is provided asa 30% aqueous dispersion as defined in Table 9 below. The methacrylicacid-ethyl acrylate (1:1) co-polymer copolymer is also provided as anaqueous dispersion as defined in Table 9 below. The first polymer filmcoat is applied until a 15% weight gain is achieved (as % w/w of theuncoated pellet core). A ‘top-coat’ consisting of ethylcellulose,methacrylic acid-ethyl acrylate (1:1) co-polymer at anethylcellulose:copolymer ratio of 1:1 based on % w/w of dry polymer andguar gum is then applied (guar gum is used at a concentration of 10% w/wof the ethylcellulose polymer content). The polymers are prepared as anaqueous dispersion and applied to the core via a top-spray fluid bedprocess. The ‘top-coat’ is applied until a 5% weight gain is achieved(as % w/w of the pellet core having the first polymer film coat). Thecomposition of ‘DR2’ is presented in Table 9.

TABLE 9 Composition of ‘DR2’ Prototype for Human PK studies Composi-tion Component Function (% w/w) Calcium oxybate monohydrate ActiveIngredient 68.99 Microcrystalline cellulose Binder & process aid  5.68Hydroxypropyl cellulose Binder and coating  4.06 polymer Hydroxypropylcellulose, low Binder  2.44 substituted (LH-31, Shin Etsu)Ethylcellulose, 30% aqueous Functional polymer  6.75 dispersion (alsocomprising film (pH independent sodium lauryl sulphate and dissolution)cetyl alcohol) Methacrylic acid - ethyl acrylate Functional polymer10.15 copolymer (1:1), Type A, 30% film (pH dependent aqueous dispersion(also dissolution, triggered comprising sodium lauryl sulphate at pH ≥5.5) and polysorbate 80) Guar gum 0.24  0.24 TEC 1.69  1.69

The in vitro dissolution of prototypes ‘DR1’ and ‘DR2’ are compared inFIG. 18. The dissolution was performed over 2 hours in 750 mL 0.1N HClat 37° C. followed by 2 hours in 1000 mL 0.04M Tris buffer pH 6.8 at 37°C. using USP type II (rotating paddle) apparatus with paddle speed of100 rpm for both buffer phases. The data demonstrates that a binarypolymer film prototype (‘DR2’) having similar total polymer content on a% w/w basis as a prototype having only an enteric film (‘DR1’) caneffectively suppress oxybate release in acid. The ‘DR2’ prototypedissolution was also tested under different pH conditions. Thedissolution profiles are presented in FIG. 19. Comparison to the ‘SR2’binary polymer prototype of Example 9 shows the increase in pH-dependentdissolution upon increasing methacrylic acid-ethylacrylate content inthe functional film coat.

The two ‘DR’ compositions were administered, in combination with anoxybate solution (IR), to healthy human volunteers two hours after thestart of a high-fat, high-calorie breakfast (dose equivalent to 4.5 gsodium oxybate). In a separate pharmacokinetic (PK) study, the ‘DR2’composition was administered in combination with an oxybate solution(IR), to healthy volunteers two hours after the start of a high-fat,high calorie breakfast at total doses equivalent to 4.5 g, 7 g and 9 gsodium oxybate (dose escalation study). The three treatmentsadministered in the dose escalation PK study are detailed in Table 10.

TABLE 10 Treatments for ‘DR2’ Dose Escalation Study TreatmentDescription 4.5 g dose 3.0 mL of oxybate solution (containing equivalentequivalent to to 1.5 g of sodium oxybate) + 4.56 g of ‘DR2’pelletssodium oxybate (containing equivalent to 3 g of sodium oxybate) 7 g dose4.67 mL of oxybate solution (containing equivalent equivalent to to 2.33g of sodium oxybate) + 7.09 g of ‘DR2’ sodium oxybate pellets(containing equivalentto 4.67 g of sodium oxybate) 9 g dose 6.0 mL ofoxybate solution (containing equivalent equivalent to to 3 g of sodiumoxybate) + 9.12 g of ‘DR2’ pellets sodium oxybate (containing equivalentto 6 g of sodium oxybate)

The PK data is presented in FIGS. 20A and 20B. The mean PK parametersfor the dose escalation study are presented in Table 11.

TABLE 11 Mean PK Parameters for ‘DR2’ Dose Escalation Study Dose CmaxAUC0-t AUC0-inf (g) N (ng/mL) Tmax (h) (ug * h/mL) (ug * h/mL) T½ (h)C8h (ug/mL) 4.5 12 40.6 2.02 142 (38.2) 148 (36.4) 0.613 (17.8) 1.19(180.6) (27.6) (0.25-4.00 ) (N = 11) (N = 11) 7 12 75.0 2.75 343 (29.2)347 (29.4) 0.671 (22.5) 5.03 (137.3) (22.5) (0.25-4.00) 9 9 104 (19.1)2.50 537 (29.5) 542 (29.2) 0.724 (26.5) 15.9 (107.3) (0.50-5.00) (% CV)except for Tmax (Median (Range))

The data indicates that the use of pH 5.5 triggered polymer film systemresults in rapid oxybate release (believed to occur in the proximalsmall intestine). The incorporation of a pH independent polymer(ethylcellulose) extended oxybate release (likely extended into thesmall intestine). Both compositions dosed incorporating the DRprototypes have the same relative bioavailability to that of thereference, Xyrem® (sodium oxybate solution). Though not wishing to bebound by any one particular theory, this is indicative that oxybaterelease from the ‘DR2’ prototype was not overextended in the smallintestine, with release within the target small intestinal absorptionwindow.

The effect of 15 minute exposure to 20% v/v ethanol in acid (0.1N HCl)on the resultant dissolution profile of the binary polymer film ‘DR2’prototype in Tris pH 6.8 buffer is presented in FIG. 21. It can be seenthat exposure to ethanol results in a significant slowing of oxybatedissolution from the coated pellet.

Example 11: Application of Ethylcellulose-Methacrylic Acid Ethylacrylate1:1 Co-Polymer Binary Polymer Film to Codeine Phosphate Pellet Cores

Multi-particulate (pellet) drug carrier cores of codeine phosphate weremade by the process of extrusion-spheronisation. The core composition isprovided in Table 11. Core components are weighed and then added to themixing bowl of a Caleva Multi-lab. The excipients (MCC, lactose, LHPC,and HPC) were pre-blended for ca. 3 min. The codeine phosphate was thenadded and blended for a further 5 min. Water was added to the mixed drycomponents until a wet mass was formed. The wet mass was extruded (dieplate diameter of 0.8 mm). The extrudate was then spheronized and driedto form the pellet core.

TABLE 11 Composition of the codeine phosphate drug carrier (pellet) coreComponent Quantity (% w/w) Codeine phosphate 10.0 Lactose (monohydrate)41.0 Microcrystalline cellulose 41.0 Hydroxypropyl cellulose  5.0Low-substituted  3.0 hydroxypropyl cellulose Water* q.s

The pellets were oven dried and then screened 0.8 mm-1.25 mm.

A binary polymer film coat consisting ethylcellulose (as the 30% aqueousdispersion, Aquacoat® ECD) and methacrylic acid-ethylacrylate 1:1co-polymer (as Eudragit® L30D-55) was applied to the codeine phosphatepellet cores at varying film thickness. The polymer film was prepared asan aqueous dispersion with polymer ratio of 1:1 (based on % w/w drypolymer) and applied as droplets to the pellet using an atomizing spraygun in a fluid bed coating unit (Calva Mini-Coater). The coated pelletswere cured under controlled temperature and humidity conditions. Thebinary polymer film was applied as a single coat. Samples were preparedhaving 15, 22 and 30% w/w (% w/w of the codeine phosphate pellet core)binary polymer film composition to evaluate the effect of the coatingfilm thickness on in-vitro dissolution characteristics in the presenceand absence of ethanol (EtOH).

FIG. 22 presents data generated for in-vitro dissolution testing of thecodeine phosphate pellet core. The dissolution test was performed usingUSP II apparatus (paddles) with 300 mL Tris buffer pH 6.8 (37° C., 100rpm).

FIG. 23 presents data for two-stage in-vitro dissolution testing of thebinary film coated codeine phosphate pellets. The dissolution test wasperformed using USP II apparatus (paddles) with 300 mL of 0.1N HCl (15minutes) followed by 300 mL of Tris buffer pH 6.8 (37° C., 100 rpm) forbetween 90 and 120 minutes. At all polymer film thicknessesinvestigated, codeine phosphate release is significantly suppressed inacid. The lag in codeine phosphate release in the Tris pH 6.8 buffer isextended with increasing polymer film thickness. In-vitro dissolutiondata is also presented following 15 minute pre-exposure of the coatedcodeine phosphate pellets to 0.1N HCl containing 20% v/v or 40% v/vEtOH. Codeine phosphate dissolution rate following subsequent transferof the EtOH exposed coated pellets to Tris pH 6.8 buffer is suppressedfor between approx. 10-15 minutes, depending on the polymer filmthickness.

FIG. 24 presents data for two-stage in-vitro dissolution testing of thebinary film coated codeine phosphate pellets following 60 minutesexposure to 0.1 N HCl containing 20% v/v EtOH. Rapid release of codeinephosphate was not triggered in the presence of 20% v/v EtOH. Codeinephosphate dissolution rate following subsequent transfer of the EtOHexposed coated pellets to Tris pH 6.8 buffer is suppressed for up to 30minutes, depending on the polymer film thickness.

Example 11: Impact of Guar Gum Containing ‘Top Coat’ on CodeinePhosphate Release from Binary Polymer Film Coated Pellets

Codeine phosphate pellet cores were made by wet massextrusion-spheronisation as described in Example 1. An aqueousdispersion of ethylcellulose and methacrylic acid-ethylacrylate 1:1co-polymer was prepared using Aquacoat® ECD and Eudragit® L30D-55respectively. The polymers were used at a 1:1 ratio (based on % w/w drypolymer) and the dispersion applied to the codeine phosphate pelletsusing a fluid bed coating process as described in Example 1. In oneembodiment, the polymer suspension was applied to a target 30% polymerweight gain (% w/w of the drug carrier core). In another embodiment, thepolymer suspension was applied to a target 40% polymer weight gain (%w/w of the drug carrier core). An additional polymer film layerincorporating the polysaccharide guar gum (“GG”) was applied to each ofthe embodiments (i.e. the codeine pellets having either a 30% or 40%weight gain binary polymer coating) to a target 5% polymer weight gain(% w/w of the drug carrier pellet having the first polymer coatapplied). This outer polymer film top coat was prepared as an aqueousdispersion of Aquacoat® ECD and Eudragit L30D-55 (1:1 dry polymer ratio)with guar gum at a level of 10% w/w of the EC polymer content. ‘Singlecoated’ codeine phosphate pellets having just the inner binary polymerfilm coating were compared to the ‘double coated’ codeine phosphatepellets having the additional outer guar gum containing polymer filmcoating.

The two-phase in vitro dissolution of codeine phosphate from the coatedpellets was determined using USP apparatus II (paddles) with 300 mL acid(0.1N HCl) medium for the first phase followed by 300 mL Tris buffer pH6.8 for the second dissolution phase (37° C., 100 RPM). Pellets with andwithout the outer GG polymer coat were exposed to the acid phase for 1hour followed by 4 hours exposure to the neutral Tris buffer. Ethanolwas added to the acid phase at either 20% v/v or 40% v/v.

The graph in FIG. 25 shows the dissolution profiles generated for thecoated codeine phosphate pellets having 30% weight gain inner binarypolymer film coating under such test conditions. No codeine phosphaterelease was detected in the acid phase dissolution test, including uponincorporation of 20% v/v EtOH for up to 2 hours. The impact of varyingEtOH concentration and exposure time during the acid-phase dissolutionon subsequent dissolution characteristics in Tris pH 6.8 buffer is wasdetermined. Increasing the EtOH concentration from 10% v/v to 20% v/vresults in more prolonged suppression of codeine release in the Tris pH6.8 buffer.

The graph in FIG. 26 shows the dissolution profiles generated for thecoated codeine phosphate pellets having 40% weight gain inner binarypolymer film coating under such test conditions. The application of thesecond coat results in more prolonged suppression of codeine release inthe presence of ethanol.

Example 12: Application of Ethylcellulose-Methacrylic Acid Ethylacrylate1:1 Co-Polymer Binary Polymer Film to Codeine Phosphate Tablet Cores

Codeine phosphate tablets were prepared by direct compression of apowder blend of codeine phosphate, Ludipress® and magnesium stearate(Table 12). All components were mixed manually for 15 minutes in a glassvial. Tablets were produced using a laboratory tablet press (GamlenTablet Press, Gamlen Tableting, UK) equipped with 5 mm round flat-facedtablet tools. Tablet blend was compressed using a pressure of 74.98 MPa(corresponding to a compression load of 150 Kg).

TABLE 12 Composition of the codeine phosphate drug carrier (tablet) coreComponent Quantity (% w/w) Codeine phosphate 50.0 Ludipress ® 49.5Magnesium stearate  0.5

A binary polymer film consisting ethylcellulose (as the 30% aqueousdispersion, Aquacoat® ECD) and methacrylic acid-ethylacrylate 1:1co-polymer (as Eudragit® L30D-55) was applied to the codeine phosphatetablet cores at varying film thickness. The polymer film was prepared asan aqueous dispersion with polymer ratio of 1:1 (based on % w/w drypolymer) and applied as droplets to the tablet using an atomizing spraygun in a fluid bed coating unit (Calva Mini-Coater). The coated tabletswere cured under controlled temperature and humidity conditions. Thebinary polymer film was applied as a single coat. Samples were preparedhaving 5 and 10% w/w (% w/w of the codeine phosphate tablet core) binarypolymer film composition to evaluate the effect of the coating filmthickness on in-vitro dissolution characteristics in the presence andabsence of ethanol (EtOH).

FIG. 27 presents data generated for in-vitro dissolution testing of thecodeine phosphate tablet core. The dissolution test was performed usingUSP II apparatus (paddles) with 300 mL Tris buffer pH 6.8 (37° C., 100rpm).

FIG. 28 presents data for two-stage in-vitro dissolution testing of thebinary film coated codeine phosphate tablets. The dissolution test wasperformed using USP II apparatus (paddles) with 300 mL of 0.1N HClfollowed by 300 mL of Tris buffer pH 6.8 (37° C., 100 rpm). At bothpolymer film thicknesses investigated, codeine phosphate release issignificantly suppressed in acid. The lag in codeine phosphate releasein the Tris pH 6.8 buffer is extended with increasing polymer filmthickness. In-vitro dissolution data is also presented following 15minute pre-exposure of the coated codeine phosphate tablets to 0.1N HClcontaining 20% v/v EtOH. Codeine phosphate dissolution rate is shown tobe reduced following subsequent transfer of the EtOH exposed coatedpellets to Tris pH 6.8 buffer.

Example 13: Application of Ethylcellulose-Methacrylic Acid Ethylacrylate1:1 Co-Polymer Binary Polymer Film to Oxycodone Hydrochloride PelletCores

Multi-particulate (pellet) drug carrier cores of oxycodone hydrochloridewere made by the process of extrusion-spheronisation. The corecomposition is provided in Table 13. The dry excipient components,namely microcrystalline cellulose (MCC), lactose monohydrate,low-substituted hydroxypropyl cellulose (L-HPC), and hydroxyl propylcellulose (HPC), were pre-blended in the mixing bowl of a CalveaMulti-lab for approximately 5 minutes before adding the oxycodonehydrochloride and blending for an additional approximately 5 minutes.Water was added to produce a wet mass suitable for extrusion andspheronisation, producing spherical pellets. The wet mass was extruded(Caleva Mini-lab) through a die plate of 0.8 mm diameter andspheronized. The pellets were dried and screened, with pellets between0.8 mm-1.25 mm used for coating.

TABLE 13 Composition of the oxycodone hydrochloride drug carrier(pellet) core Component Quantity (% w/w) Oxycodone hydrochloride 10.0MCC 41.0 Lactose monohydrate 41.0 L-HPC  3.0 HPC  5.0

A binary polymer film consisting ethylcellulose (as the 30% aqueousdispersion, Aquacoat® ECD) and methacrylic acid-ethylacrylate 1:1co-polymer (as Eudragit® L30D-55) was applied to the oxycodonehydrochloride pellet cores at varying film thickness. The polymer filmwas prepared as an aqueous dispersion with polymer ratio of 1:1 (basedon % w/w dry polymer) and applied as droplets to the tablet using anatomizing spray gun in a fluid bed coating unit (Calva Mini-Coater). Thecoated tablets were cured under controlled temperature and humidityconditions. The binary polymer film was applied as a single coat.Samples were prepared having 15%, 22% and 30% w/w (% w/w of the codeinephosphate tablet core) binary polymer film composition to evaluate theeffect of the coating film thickness on in-vitro dissolutioncharacteristics in the presence and absence of ethanol (EtOH).

FIG. 29 presents data generated for in-vitro dissolution testing of theoxycodone hydrochloride pellet core. The dissolution test was performedusing USP II apparatus (paddles) with 300 mL Tris buffer pH 6.8 (37° C.,100 rpm).

FIG. 30 presents data for two-stage in-vitro dissolution testing of thebinary film coated oxycodone hydrochloride pellets. The dissolution testwas performed using USP II apparatus (paddles) with 300 mL of 0.1N HClfollowed by 300 mL of Tris buffer pH 6.8 (37° C., 100 rpm). At allpolymer film thicknesses investigated, oxycodone hydrochloride releaseis significantly suppressed in acid. The lag in oxycodone hydrochloriderelease in the Tris pH 6.8 buffer is extended with increasing polymerfilm thickness. In-vitro dissolution data is also presented following 15minute pre-exposure of the coated oxycodone hydrochloride pellets to0.1N HCl containing 20% v/v EtOH. Oxycodone hydrochloride dissolutionrate following subsequent transfer of the EtOH exposed coated pellets toTris pH 6.8 buffer is suppressed for between approx. 10-30 minutes,depending on the polymer film thickness.

Example 14: Impact of Guar Gum Containing ‘Top Coat’ on OxycodoneHydrochloride Release from Binary Polymer Film Coated Pellets

Codeine phosphate pellet cores were made by wet massextrusion-spheronisation as described in Example 4. An aqueousdispersion of ethylcellulose and methacrylic acid-ethylacrylate 1:1co-polymer was prepared using Aquacoat® ECD and Eudragit® L30D-55respectively. The polymers were used at a 1:1 ratio (based on % w/w drypolymer) and the dispersion applied to the oxycodone hydrochloridepellets using a fluid bed coating process as described in Example 4. Thepolymer suspension was applied to a target 30% polymer weight gain (%w/w of the drug carrier core). An additional polymer film layerincorporating the polysaccharide guar gum (“GG”) was applied to thecoated pellets (i.e. the oxycodone pellets having a 30% weight gainbinary polymer coating) to a target 5% polymer weight gain (% w/w of thedrug carrier pellet having the first polymer coat applied). This outerpolymer film top coat was prepared as an aqueous dispersion of Aquacoat®ECD and Eudragit L30D-55 (1:1 dry polymer ratio) with guar gum at alevel of 10% w/w of the EC polymer content. ‘Single coated’ oxycodoneHCl pellets having just the inner binary polymer film coating werecompared to the ‘double coated’ oxycodone HCl pellets having theadditional outer guar gum containing polymer film coating.

The two-phase in vitro dissolution of oxycodone HCl from the coatedpellets was determined using USP apparatus II (paddles) with 300 mL acid(0.1N HCl) medium for the first phase followed by 300 mL Tris buffer pH6.8 for the second dissolution phase (37° C., 100 RPM). Pellets with andwithout the outer GG polymer coat were exposed to the acid phase for 1hour followed by 3 hours exposure to the neutral Tris buffer. Ethanolwas added to the acid phase at 20% v/v. The graph in FIG. 31 shows thedissolution profiles generated for the coated oxycodone HCl pelletsunder such test conditions.

Example 15: Application of Ethylcellulose-Methacrylic Acid Ethylacrylate1:1 Co-Polymer Binary Polymer Film to Oxycodone Hydrochloride TabletCores

Oxycodone hydrochloride tablets were prepared by direct compression of apowder blend of oxycodone hydrochloride, Ludipress® and magnesiumstearate (Table 14). All components were mixed manually for 15 minutesin a glass vial. Tablets were produced using a laboratory tablet press(Gamlen Tablet Press, Gamlen Tableting, UK) equipped with 5 mm roundflat-faced tablet tools. Tablet blend was compressed using a pressure of74.98 MPa (corresponding to a compression load of 150 Kg).

TABLE 14 Composition of the oxycodone hydrochloride drug carrier(tablet) core Component Quantity (% w/w) Oxycodone hydrochloride 50.0Ludipress ® 49.5 Magnesium stearate  0.5

A binary polymer film consisting ethylcellulose (as the 30% aqueousdispersion, Aquacoat® ECD) and methacrylic acid-ethylacrylate 1:1co-polymer (as Eudragit® L30D-55) was applied to the oxycodone HCltablet cores at varying film thickness. The polymer film was prepared asan aqueous dispersion with polymer ratio of 1:1 (based on % w/w drypolymer) and applied as droplets to the tablet using an atomizing spraygun in a fluid bed coating unit (Calva Mini-Coater). The coated tabletswere cured under controlled temperature and humidity conditions. Thebinary polymer film was applied as a single coat. Samples were preparedhaving 10 and 20% w/w (% w/w of the oxycodone HCl tablet core) binarypolymer film composition to evaluate the effect of the coating filmthickness on in-vitro dissolution characteristics in the presence andabsence of ethanol (EtOH).

FIG. 32 presents data generated for in-vitro dissolution testing of theoxycodone HCl tablet core. The dissolution test was performed using USPII apparatus (paddles) with 300 mL Tris buffer pH 6.8 (37° C., 100 rpm).

FIG. 33 presents data for two-stage in-vitro dissolution testing of thebinary film coated oxycodone HCl tablets. The dissolution test wasperformed using USP II apparatus (paddles) with 300 mL of 0.1N HClfollowed by 300 mL of Tris buffer pH 6.8 (37° C., 100 rpm). At bothpolymer film thicknesses investigated, oxycodone HCl release issignificantly suppressed in acid. The lag in oxycodone release in theTris pH 6.8 buffer is extended with increasing polymer film thickness.In-vitro dissolution data is also presented following 60 minutepre-exposure of the coated codeine phosphate tablets to 0.1N HClcontaining 20% v/v EtOH. No increase in oxycodone release was detectedduring exposure to 20% v/v EtOH. Upon subsequent transfer of the tabletsto non-EtOH containing Tris pH 6.8 buffer, oxycodone dissolution rate isshown to be slightly reduced for the tablet having 10% w/w polymer filmcoating, with the thicker 20% w/w polymer film coating generating anapprox. further 30 min extension to the lag in oxycodone release upontransfer to Tris buffer (from 90 min to 120 min).

All patents, patent applications and publications mentioned herein arehereby incorporated by reference in their entirety.

Although disclosure has been provided in some detail by way ofillustration and example for the purposes of clarity of understanding,it will be apparent to those skilled in the art that various changes andmodifications can be practiced without departing from the spirit orscope of the disclosure. Accordingly, the foregoing descriptions andexamples should not be construed as limiting.

1. A pharmaceutical formulation comprising: at least one population ofcoated drug carrier cores comprising a drug carrier core comprising atleast one therapeutic agent, and a coating disposed over the drugcarrier core, and wherein the coating comprises a polymer blend ofcellulose and polymethacrylate polymers.
 2. The formulation of claim 1,wherein the polymer blend comprises ethyl cellulose and at least onepolymethacrylate.
 3. The formulation of claim 2, wherein the ethylcellulose and the polymethacrylate polymer are present at a weight ratioof ethyl cellulose:polymethacrylate polymer from 50:1 to 1:50, 25:1 to1:25, 10:1 to 1:10, 5:1 to 1:5 or 3:1 to 1:3.
 4. The formulation of anyone of claims 1-3, wherein the polymer blend comprises at least twoalcohol-soluble polymers; at least one alcohol-soluble polymer and atleast one alcohol-insoluble polymer; or at least two alcohol-insolublepolymers.
 5. The formulation of any one of claims 1-4, wherein thepolymer blend comprises at least one polymer with pH-dependentdissolution and at least one polymer with pH-independent dissolutionproperties.
 6. The formulation of any one of claims 1-4, wherein thepolymer blend comprises at least two polymers with pH-independentdissolution properties.
 7. The formulation of any one of claims 1-4,wherein the polymer blend comprises at least two polymers withpH-dependent dissolution properties.
 8. The formulation of claim 5 or 6,wherein the polymers with pH-independent dissolution properties areselected from ethyl cellulose, ethyl acrylate-methyl methacrylateco-polymers, ethyl acrylate-methyl methacrylate-trimethylammonioethylmethacrylate chloride co-polymers, or combinations thereof.
 9. Theformulation of claim 5 or 7, wherein the polymers with pH-dependentdissolution properties are selected from methacrylic acid-ethyl acrylateco-polymers, butyl methacrylate-(2-dimethylaminoethyl)methacrylate-methyl methacrylate co-polymers, methacrylic acid methylmethacrylate co-polymers, methyl acrylate-methyl methacrylatemethacrylic acid co-polymers, or combinations thereof.
 10. Theformulation of claim 9, wherein the methacrylic acid-ethyl acrylateco-polymer is methacrylic acid-ethyl acrylate co-polymer 1:1.
 11. Theformulation of any one of claims 1-10, wherein the coating is a firstcoating and the formulation further comprises a second coatingcomprising at least one polymer, wherein the second coating is disposedover the first coating.
 12. The formulation of claim 11 wherein thesecond coating comprises a single polymer.
 13. The formulation of claim12 wherein the single polymer is a cellulose polymer.
 14. Theformulation of claim 13 wherein the cellulose polymer is ethylcellulose.15. The formulation of claim 11 wherein the second coating comprises ablend of at least two polymers.
 16. The formulation of claim 15 whereinthe blend of at least two polymers comprises a cellulose polymer and apolymethacrylate polymer.
 17. The formulation of claim 16 wherein theblend of at least two polymers comprises ethyl cellulose and methacrylicacid-ethyl acrylate co-polymer
 18. The formulation of any one of claims11-17, wherein the second coating further comprises a polysaccharide gumsuch as acacia gum, guar gum, tragacanth gum or xanthan gum.
 19. Theformulation of claim 18, wherein the polysaccharide gum is acacia gum,guar gum, tragacanth gum or xanthan gum or mixtures thereof.
 20. Theformulation of claim 19 wherein the second coating further comprisesguar gum.
 21. The formulation of any one of claims 11-17, wherein thesecond coating comprises an alginic acid, or salt thereof.
 22. Theformulation of any one of claim 12, 16 or 17 where in the second coatingfurther comprises guar gum, and wherein the guar gum is present at 1-15%w/w/ of the cellulose polymer.
 23. The formulation of claim 22 where inthe guar gum is present at 5-10% w/w/ of the cellulose polymer.
 24. Aformulation as recited any one of claims 1-23, wherein the therapeuticagent is selected from GHB, paracetamol, codeine or oxycodone andpharmaceutically acceptable salts, hydrates, tautomers, solvates,prodrugs, isotopologues and complexes of GHB, paracetamol, codeine oroxycodone.
 25. The formulation of claim 24 wherein the therapeutic agentis GHB, or pharmaceutically acceptable salts, hydrates, tautomers,solvates, prodrugs, isotopologues and complexes thereof.
 26. Theformulation of claim 25, wherein said the therapeutic agent is a GHBsalt is selected from sodium oxybate, calcium oxybate, potassiumoxybate, or combinations thereof.
 27. The formulation of claim 25,wherein said the therapeutic agent is a GHB salt is selected from sodiumoxybate, calcium oxybate, potassium oxybate, magnesium oxybate, orcombinations thereof.
 28. The formulation of any one of claims 1-27,wherein the formulation is resistant to alcohol-induced dose dumping.29. The formulation of claim any one of claims 1-28, wherein at leastone population of coated drug carrier cores provide an immediate releaseprofile or modified release profile.
 30. The formulation of any one ofclaims 1-29, wherein at least one population of drug carrier corescomprises immediate release coated drug carrier cores and provides animmediate release profile of the therapeutic agent in the absence ofethanol.
 31. The formulation of claim 30, wherein the immediate releaseprofile provides between about 70% and about 100% release of thetherapeutic agent after about 5 minutes to about 60 minutes of being inan aqueous buffer.
 32. The formulation of any one of claims 1-31,wherein at least one population of coated drug carrier cores comprisessustained release coated drug carrier cores, wherein the sustainedrelease coated drug carrier cores provide a sustained release profile ofthe therapeutic agent in the absence of ethanol.
 33. The formulation ofclaim 32, wherein the sustained release coated cores release about 10%to about 50% of the therapeutic agent within about 1 hour in an aqueousbuffer, between about 20% to about 70% of the therapeutic agent withinabout 2 hours to about 4 hours in an aqueous buffer, and between about50% to about 80% of the therapeutic agent within about 4 hours to about10 hours in an aqueous buffer.
 34. The formulation of any one of claims1-33, wherein at least one population of drug carrier cores comprisesdelayed release coated drug carrier cores, wherein the delayed releasecoated drug cores provide a delayed release profile of the therapeuticagent in the absence of ethanol.
 35. The formulation of claim 34 whereinthe delayed release coated drug cores release about 0% to 40% of thetherapeutic agent within about 1 hour to about 2 hours in an acidicaqueous buffer.
 36. The formulation of claim 35, wherein after exposureto the acidic aqueous buffer, the population of delayed release drugcarrier cores is exposed to a non-acidic aqueous solution and release ofthe therapeutic agent increases to between about 50% to about 100%release within about 1 hour of being in the non-acidic aqueous solution;or to between about 10% to about 70% release within about 1 hour toabout 4 hours of being in the non-acidic aqueous solution.
 37. Theformulation of any one claims 1-36, wherein at least one population ofcoated drug carrier cores provides an immediate release rate or amodified release rate, and the release rate when measured using a firstin vitro dissolution test in the absence of ethanol and the release ratewhen using a second vitro dissolution test in the presence of about 5%to about 40% ethanol (v/v) are substantially the same, wherein, otherthan the absence or presence ethanol, the first in vitro dissolutiontest and the second in vitro dissolution test are the same.
 38. Theformulation of any one of claims 1-36, wherein at least one populationof coated drug carrier cores provides an immediate release rate or amodified release rate, and wherein the release rate when measured usinga first in vitro dissolution test in the presence of about 5% to about40% ethanol (v/v) is decreased as compared the release rate measuredwhen using a second vitro dissolution test in the absence of ethanol,wherein, other than the absence or presence ethanol, the first in vitrodissolution test and the second in vitro dissolution test are the same.39. The formulation of claim 27, wherein the release rate demonstratesan ethanol concentration-dependent decrease in release when exposed tobetween about 5% to about 40% ethanol.
 40. The formulation of claim 27or 28, wherein the release rate of the therapeutic agent is measuredusing an in vitro dissolution test comprising an acidic aqueous bufferand an optional, subsequent, non-acid aqueous buffer, and the about 5%to about 40% ethanol (v/v) is present in the acidic aqueous buffer. 41.The formulation of any one of claims 1-40, wherein the release rate ofthe therapeutic agent is measured in vitro using a US Pharmacopeia (USP)Dissolution Apparatus 2 (paddle) operated at 100 RPM, by the steps of:(a) Stage I: exposing the formulation to 750 mL solution of 0.1Nhydrochloric acid (HCl) (approximately pH 1.2) 37° C. for up to 2 hours;Stage II: adding 250 mL of 0.316 Tris buffer (degassed andpre-equilibrated to 37° C.) and adjust the pH to 6.8 using 25% HCl; andexpose the formulation for 2 hours; (c) drawing samples at prescribedintervals; (d) filtering the sample through a suitable filter; and, (e)determining the drug concentration using high performance liquidchromatography (HPLC); wherein when the release rate is measured atabout 5% to about 40% v/v ethanol, the solution of Stage I furthercomprises about 5% to about 40% v/v ethanol.
 42. The formulation of anyone of claims 1-41, wherein one or more of the coatings furthercomprises a plasticizer.
 43. The formulation of claim 42, wherein theplasticizer is selected from acetyltributyl citrate, acetyltriethylcitrate, benzyl benzoate, dibutyl phthalate, dibutyl sebacate, diethylphthalate, dimethyl phthalate, glyceryl triacetate, polyethylene glycol,propylene glycol, pyrrolidone, triacetin, triethyl citrate and tributylcitrate.
 44. A formulation of GHB comprising, at least one population ofcoated drug carrier cores, wherein the drug carrier cores comprise, acore having between 70% and 90% GHB salt, 1-20% microcrystallinecellulose, and 1-10% hydroxypropylcellulose; and, a coating comprisingethylcellulose and methacrylic acid-ethyl acrylate co-polymer 1:1 at aratio of ethylcellulose:copolymer of 3:1 to 1:3, wherein the coating ispresent at about 5% to about 60% w/w.
 45. A formulation of GHBcomprising, at least one population of coated drug carrier cores,wherein the drug carrier cores comprise, a core having between 70% and90% calcium GHB, 1-20% Avicel 101, 0-3% L-HPC LH31, and 1-10%Hydroxypropylcellulose 300-600 CPS, a first coat comprising Aquacoat ECD30 and Eudragit L30D55, Eudragit L100-55, or a combination thereof,wherein the coating is present at about 5-60% w/w.
 46. The formulationof claim 44 or 45, wherein the coated drug carrier cores furthercomprise a second coating comprising either a) Aquacoat ECD 30(ethylcellulose) and guar gum; or b) ethylcellulose, methacrylicacid-ethyl acrylate (1:1) co-polymer and guar gum, wherein at a ratio ofethylcellulose:copolymer of 3:1 to 1:3, and wherein the second coatingis present at about 1% to about 50% w/w, and is disposed over the firstcoating. the formulation of claim 45, wherein the guar gum is present at1-15% w/w of the ethylcellulose.
 47. The formulation of claim 46,wherein the guar gum is present at 1-15% w/w of the ethylcellulose 48.The formulation of claim 47, wherein the guar gum is present at 5-10%w/w of the ethylcellulose.
 49. A formulation of any of claims 1 to 48,wherein the first coating is about 5-60% by weight of the core.
 50. Aformulation of claim 49 wherein the first coating is from about 5-10%,5-15%, 5-20%, 5-25%, 5-30%, 5-35%, 5-40%, 5-45%, 5-50%, 5-55%, 10-15%,10-20%, 10-25%, 10-30%, 10-35%, 10-40%, 10-45%, 10-50%, 10-55%, 10-55%,10-60, 15-20%, 15-25%, 15-30%, 15-35%, 15-40%, 15-45%, 15-50%, 15-55%,15-60%, 20-25%, 20-30%, 20-35%, 20-40%, 20-45%, 20-50%, 20-55%, 20-60%,25-30%, 25-35%, 25-40%, 25-45%, 25-50%, 25-55%, 25-60%, 30-35%, 30-40%,30-45%, 30-50%, 30-55%, 30-60%, 35-40%, 35-45%, 35-50%, 35-55%, 35-60%,40-45%, 40-50%, 40-55%, 40-60%, 45-50%, 45-55%, 45-60%, 50-55%, 50-60%,or 55-60% by weight of the core.
 51. A formulation of any of claims 11to 450, wherein the second coating is about 1-50% by weight of the coreand a first coating.
 52. A formulation of claim 51, wherein the secondcoating is from about 1-5%, 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 5-35%,5-40%, 5-45%, 5-50%, 5-55%, 10-15%, 10-20%, 10-25%, 10-30%, 10-35%,10-40%, 10-45%, 10-50%, 15-20%, 15-25%, 15-30%, 15-35%, 15-40%, 15-45%,15-50%, 15-55%, 15-60%, 20-25%, 20-30%, 20-35%, 20-40%, 20-45%, 20-50%,20-55%, 20-60%, 25-30%, 25-35%, 25-40%, 25-45%, 25-50%, 30-35%, 30-40%,30-45%, 30-50%, 30-55%, 30-60%, 35-40%, 35-45%, 35-50%, 40-45%, 40-50%,or 45-50% by weight of the core.
 53. A formulation of claim 49-52,wherein the first coating comprises ethylcellulose and methacrylicacid-ethyl acrylate co-polymer 1:1 at a coating thickness of from about5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 5-35%, 5-40%, 5-45%, 5-50%, 5-55%,10-15%, 10-20%, 10-25%, 10-30%, 10-35%, 10-40%, 10-45%, 10-50%, 10-55%,10-55%, 10-60, 15-20%, 15-25%, 15-30%, 15-35%, 15-40%, 15-45%, 15-50%,15-55%, 15-60%, 20-25%, 20-30%, 20-35%, 20-40%, 20-45%, 20-50%, 20-55%,20-60%, 25-30%, 25-35%, 25-40%, 25-45%, 25-50%, 25-55%, 25-60%, 30-35%,30-40%, 30-45%, 30-50%, 30-55%, 30-60%, 35-40%, 35-45%, 35-50%, 35-55%,35-60%, 40-45%, 40-50%, 40-55%, 40-60%, 45-50%, 45-55%, 45-60%, 50-55%,50-60%, or 55-60% by weight of the core.
 54. A method of treatment orprophylaxis of a disease, disorder or symptom comprising administrationof a formulation of any one of claims 1-53 to a patient in need thereof,wherein the disease, disorder or symptom is selected from the groupconsisting of sleeping disorders, drug abuse, alcohol and/or opiatewithdrawal, a reduced level of growth hormone, anxiety, analgesia,effects in certain neurological disorders, Parkinson's Disease,depression, fibromyalgia, certain endocrine disturbances and tissueprotection following hypoxia/anoxia such as in stroke or myocardialinfarction, or an increased level of intracranial pressure, excessivedaytime sleepiness, cataplexy, sleep paralysis, apnea, narcolepsy, sleeptime disturbances, REM sleep behavior disorder (RBD), hypnagogichallucinations, sleep arousal, insomnia, idiopathic hypersomnia,essential tremor and nocturnal myoclonus.
 55. Use of a formulation inany one of claims 1-53, for treatment or prophylaxis of a disease,disorder or symptom, such as sleeping disorders, drug abuse, alcoholand/or opiate withdrawal, a reduced level of growth hormone, anxiety,analgesia, effects in certain neurological disorders, such asParkinson's Disease, depression, fibromyalgia, certain endocrinedisturbances and tissue protection following hypoxia/anoxia such as instroke or myocardial infarction, or an increased level of intracranialpressure, excessive daytime sleepiness, cataplexy, sleep paralysis,apnea, narcolepsy, sleep time disturbances (including, for example,those resulting from stress or trauma such as post-traumatic stressdisorder and/or traumatic brain injury), REM sleep behavior disorder(RBD), hypnagogic hallucinations, sleep arousal, insomnia (includingvarious types of insomnia such as, for example, idiopathic hypersomnia),essential tremor and nocturnal myoclonus in a human patient.
 56. Aprocess for making a formulation of any one of claims 1-53.